Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2020 / Article

Review Article | Open Access

Volume 2020 |Article ID 3656419 | https://doi.org/10.1155/2020/3656419

Nathan Earl Rainey, Aoula Moustapha, Patrice Xavier Petit, "Curcumin, a Multifaceted Hormetic Agent, Mediates an Intricate Crosstalk between Mitochondrial Turnover, Autophagy, and Apoptosis", Oxidative Medicine and Cellular Longevity, vol. 2020, Article ID 3656419, 23 pages, 2020. https://doi.org/10.1155/2020/3656419

Curcumin, a Multifaceted Hormetic Agent, Mediates an Intricate Crosstalk between Mitochondrial Turnover, Autophagy, and Apoptosis

Academic Editor: Tullia Maraldi
Received23 Nov 2019
Revised01 Mar 2020
Accepted25 May 2020
Published20 Jul 2020

Abstract

Curcumin has extensive therapeutic potential because of its antioxidant, anti-inflammatory, and antiproliferative properties. Multiple preclinical studies in vitro and in vivo have proven curcumin to be effective against various cancers. These potent effects are driven by curcumin’s ability to induce G2/M cell cycle arrest, induce autophagy, activate apoptosis, disrupt molecular signaling, inhibit invasion and metastasis, and increase the efficacy of current chemotherapeutics. Here, we focus on the hormetic behavior of curcumin. Frequently, low doses of natural chemical products activate an adaptive stress response, whereas high doses activate acute responses like autophagy and cell death. This phenomenon is often referred to as hormesis. Curcumin causes cell death and primarily initiates an autophagic step (mitophagy). At higher doses, cells undergo mitochondrial destabilization due to calcium release from the endoplasmic reticulum, and die. Herein, we address the complex crosstalk that involves mitochondrial biogenesis, mitochondrial destabilization accompanied by mitophagy, and cell death.

Curcumin, or (1E,6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, is a symmetric molecule also called diferuloyl methane (MW 368.38 g·mol-1) extracted from the dietary spice curcuma, historically used in Asian food and traditional medicine [1]. As previously described curcumin [2, 3] three chemical entities structure the molecule:2 o-methoxyphenol connected by a seven-carbon linker with an α,β-unsaturated diketone moiety (Figure 1(a)).The resonance structure inside the molecule is responsible for its participation in many electron transfer reactions.

Almost a century after its isolation from turmeric, Lampe in 1913 [4] published the synthesis of curcumin in a series of steps starting with carbomethoxyferuloyl chloride and ethyl acetoacetate. Later, Pabon described a simple method for the synthesis of curcumin with high yields that is still in use today [5]. Patented processes indicating the use of B2O3, trialkylborate, and n-butylamine along with inert organic amide solvents have since improved yields [68] (Figure 2(a)). High-performance liquid chromatography (HPLC) is efficiently used for the detection and quantification of curcumin [9].

Curcumin is an electron donor and stabilizes its chemical structure by redistribution and resonance of the π electron cloud [1]. The extended conjugation confers UV-visible absorption properties (250-270 nm and 350-450 nm). So, curcumin fluoresces with emission starting at 470 nm. These optical properties are used for the isolation and purification of curcumin by various techniques and fluorescence which enable the monitoring of very low amounts of curcumin and related metabolites in plasma and urine in the range of 2.5 ng/mL [911]. Curcumin can also be excited at 488 nm with a lower fluorescent yield emission in the 500-550 nm range for detection in flow cytometry and confocal microscopy as we described before [2]. Curcumin is a weak Brönsted acid, with three labile protons and accordingly three pKa values—which can be estimated by both NMR and absorption spectrometry—corresponding to three prototropic equilibria (Figure 2(b)).

A key active site of curcumin for biological reactions is the diketo group, which acts as the primary hydrogen affinity site at physiological pH [1, 12]. The diketo group displays keto-enol tautomerism to reach prototropic equilibrium [12]. In addition to this enol (A-OH) site, the two phenol-OH locations appear to be more resistant to oxidation, but can undergo oxidation by electron transfer and hydrogen abstraction at more alkaline pH. Curcumin is a hydrophobic molecule with a log value of 3.0 at neutral pH [13]. Therefore, curcumin is not easily soluble in physiological media and exhibits poor distribution and bioavailability [14].

As a whole, curcumin acts as a hydrophobic reducing agent and scavenges many reactive oxygen species (ROS) (Figure 2(c)) [14]. Phenoxyradicals formed can be regenerated by other H+ donors like ascorbic acid, for consecutive ROS elimination. Curcumin is as efficient in the removal of radicals as well-known antioxidants—thiols, vitamin A, vitamin C, and vitamin E—and mimics the function of superoxide dismutase [13].

The hydrogen donor site α,β-unsaturated β-diketo moiety is also considered the breakdown point in the curcumin structure, where curcumin hydrolysis and degradation take place essentially in aqueous media. Indeed, ninety percent of curcumin degrades within half an hour in water [15], giving rise by hydrolysis to several products, i.e., ferulic acid, ferulic aldehyde, and feruloyl methane.

The rate of curcumin hydrolysis significantly decreases when the diketo reaction site is complexed to lipids, peptides, proteins, surfactants, and other molecular structures, a situation occurring both in biological fluids and within cells [16]. Accordingly, curcumin solutions are more stable in culture media containing fetal calf serum (FCS), and evidence shows that once curcumin is in the bloodstream, hydrolytic degradation is abolished since the diketo function is occupied through binding to plasma proteins and other biomolecules [17]. On the other hand, even though hydrolytic degradation of curcumin scarcely happens in vivo, it is subject, once absorbed, to fast enzyme-mediated metabolism leading to hydrophilic metabolites [15]. Pathways have been proposed for the metabolism of hydrophobic curcumin to hydrophilic metabolites [13].

Curcumin is reduced to tetra-, hexa-, and octa-hydrocurcumins, and its two phenolic groups are conjugated to produce either curcumin glucuronide or curcumin sulfate [15] (Figure 1(b)).

The reduction or conjugation of curcumin is thought to be a slow process allowing curcumin to accumulate in cells and exert activity [18]. Glucuronidation of curcumin and curcuminoids, produced by the phase II detoxifying pathway in liver, results in the production of various curcuminoid-glucuronides with reduced activity [19]. However, as phase I enzymes are more expressed than phase II, curcumin absorption in liver induces transcriptional responses that enhance the antioxidant capacity of hepatic and extrahepatic tissues, which could explain some of curcumin’s chemopreventive properties.

Other properties arise from a possible nucleophilic addition reaction between the unsaturated ketone of curcumin and anions like A-OH, A-SH, and A-SeH from other molecules [13]. As a result, curcumin can bind to various proteins. For instance, conjugation with glutathione-SH results in the depletion of the glutathione pool and the antioxidant defense system (ADS) in cells. In this regard, the depletion of glutathione molecules suggests that curcumin acts as a prooxidant contributor in some conditions [15]. But, depending on the concentration, this stress triggers an adaptive response boosting the glutathione production and other components of ADS. Once a threshold is reached, curcumin drives in parallel endoplasmic reticulum (ER) stress causing calcium release that can result in mitochondrial destabilization, producing more ROS and eventually overcoming the antioxidant defense system (ADS) of cells. This biphasic response is a key feature of an hormetic response discussed previously [2, 3, 20].

2. Cellular Uptake and Intracellular Distribution of Curcumin

Cellular distribution of curcumin has not attracted much attention, even though curcumin fluorescence can be used to localize it within cells, which is of great interest in understanding its mode of action. The effects of curcumin, including the drop in and the production of ROS, do not appear to be the consequences of its direct action on mitochondria [2, 3].Indeed, the very early release of calcium into the cytoplasm following curcumin treatment led us to investigate potential interactions between curcumin and ER, which contains the main cellular pool of free calcium. Cellular uptake was observed by confocal microscopy in HuH-7 cells incubated with 20 μM curcumin (without pH indicator) after different time intervals ranging from 0 to 48 hours.As shown in Figure 3, Curcumin fluorescence colocalized with ER red staining [3]. We also evaluated, by Amnis®, curcumin fluorescence with the pattern of lysosome staining assessed with LysoTracker Red DN99 and observed that some lysosomes presented both types of fluorescence, whereas others did not (Figure 4).

This suggests that curcumin interactions with lysosomes are strictly dependent on its concentration, a situation that can be explained by an additive pathway which may cooperate with the ER/calcium/mitochondrial pathway previously described [2, 3, 21].

3. Curcumin-Metal Complexation Reactions

The hydrogen bonding and hydrophobicity of curcumin associated with its aromatic ends and tautomeric structures along with the flexibility of the linker are responsible for noncovalent interactions. Curcumin forms strong complexes with most of the known metal ions [1]. The α,β-unsaturated β-diketo moiety of curcumin behaves as a chelating agent. Over the last decade, many papers have been published on metal-curcumin complexes, including examples of interactions [18, 19, 2227] and review papers [1, 23]. Although it is well known that curcumin reduces metal toxicity in living systems through complexation, the actual role of these metal complexes of curcumin in cellular physiology is quite complex and unclear.

More precisely, curcumin can act as a chelating agent (presumably bidentate) for Fe2+ [28], Fe3+ [29, 30], and Cu2+ [14, 31] (Figure 5). As a chelator of iron, curcumin is supposed to alleviate H2O2 reduction, which produces hydroxyl radicals (HO) and other ROS [28].

The α,β-unsaturated β-diketo moiety of curcumin forms chelates with transition metals, thereby reducing metal-induced toxicity, and some metal complexes exhibit improved antioxidant activity as enzyme mimics. Specific analogs are being developed to improve these activities and have been summarized recently [1, 32, 33].

In this broad literature, most of the promising medicinal applications of metal-curcumin complexes are in the field of anticancer activity with selective cytotoxicity and antineurodegenerative disorders with antioxidative/neuroprotective activity [3438]. Curcumin-metal complexes not only modify the physicochemical properties of curcumin but also affect the biological reactivity of the metals. From our observations, the proautophagic and proapoptotic activities of curcumin [2, 39] are abolished by complexation [20]. Complexation with other metals like Cu2+ and Mn2+ can also reduce their toxicity, and some of the curcumin complexes behave as new antioxidants like superoxide dismutase mimics [14, 15, 17, 18, 31, 40, 41].

In fact, all the metals involved in Alzheimer’s disease can form stable complexes with curcumin [18, 19, 42]. For example, curcumin forms three different types of complexes with Al3+, a major suspect in Alzheimer’s pathophysiology. In 1 : 1 stoichiometry, the Al3+-curcumin complex has less DNA-binding affinity than free Al3+, which is recognized as a hallmark in reducing the development of Al3+-induced Alzheimer’s disease [19, 42]. There are many other complexes: Ga2+-curcumin complexes developed as innovative bioceramics [43]; Zn3+-curcumin with anticancer, gastroprotective, and antidepressant effects in rats [44, 45]; Au2+-curcumin (five-coordinated form), which shows antiarthritic activity in vivo [46]; and vanadyl-curcumin ([VO(Cur)2]2+), which has antioxidant and antirheumatic activity [47]. Also, it is evident that curcumin reduces the toxicity of heavy metals like Hg2+, Cd2+, and Pb2+ through metal coordination, with significant reduction in oxidative stress [25, 4851].

To our knowledge, curcumin-Fe complexes are unable to induce cell death as curcumin alone does [20]. What is truly interesting is that curcumin-metal complexes may also exhibit hormetic behavior, which extends the range of action of curcumin’s biological activity [39].

4. Curcumin Reactivity with Reactive Oxygen Species

Curcumin, with its three functional groups—one diketone moiety and two phenolic groups, sustains many reactions like hydrogen donation leading to oxidized curcumin, reversible and irreversible nucleophilic addition, hydrolysis, or enzymatic reactions [32].

Curcumin is an excellent scavenger of most ROS, a feature that partially confers its antioxidant behavior in biological systems (Figure 6). ROS consist of both free radical oxidants and molecular oxidants [29, 5258].

Free radical oxidants participate in electron transfer reactions and in hydrogen abstraction. All three active sites of curcumin may be oxidized by electron transfer and hydrogen abstraction. All three sites in curcumin can be oxidized, but the easiest abstractable hydrogen is from the phenol group, resulting in the formation of phenoxyl radicals, which are stabilized across the keto-enol structure. The most interesting example is the fact that peroxyl radicals (ROO) can react with curcumin and form phenoxyl radicals that are less reactive than peroxyl radicals, thereby enhancing protection against ROS-induced oxidative stress. Soluble antioxidants like ascorbic acid confer upon the molecule a chain-breaking antioxidant capacity like that of vitamin E [53]. Curcumin scavenging of several other free radical ROS such as hydroxyl radicals, superoxide radicals, and alkoxy radicals has been described [53, 55, 57, 58]. The reaction of curcumin with superoxide radicals—generally produced at the inner mitochondrial membrane and not diffusible—is as efficient as other antioxidants and leads to catalytic degradation of superoxide in which curcumin acts as a superoxide dismutase mimetic [55].

ROS behavior and function are interestingly bizarre as they are the main regulators in the initiation and regulation of autophagy, cell survival, and cell apoptosis [59]. Despite that antioxidant activity in normal cells and prooxidant activity in cancerous cells have been established, there is still no clear biochemical explanation to this dual function of curcumin [1]. Nevertheless, this selective dual function suggests that curcumin is a potential adjuvant in chemotherapy and radiotherapy protocols to enhance cancer sensitivity and reduce toxicity to normal tissues [6062].

In cancer cells, curcumin induces ER membrane destabilization, releasing Ca2+, activating downstream signaling proteins such as C/EBP homologous protein (CHOP), and upregulating ER transmembrane proteins (PERK, IRE-1α, ATF6) and proapoptotic Bcl-2 protein. These proteins are mediators of ER homeostasis, and excessive accumulation in the ER activates apoptosis [63, 64]. Over a certain threshold, curcumin induces ER-mediated apoptosis, while lower levels of ROS for the same pathway—under moderate stress like hypoxia—stay in the homeostatic range and allow cancer cells to duck apoptosis [65].

Because cancer cells maintain high levels of ROS—as a consequence of high ROS production or a decline of ROS scavenging capacity—they are selectively vulnerable to further ROS augmentation caused by an exogenous agent like curcumin [66]. Curcumin and new curcumin derivatives at high intracellular concentration (≥2.5 μM) also behave like proapoptotic agents through mitochondria-dependent mechanisms that induce cell death (mainly apoptosis) in a wide range of cell types [6771]. Furthermore, curcumin exerts antioxidant effects upon mitochondria via different mechanisms, i.e., decreased production of ROS and upregulation of antioxidant enzymes [7275].

Enhanced ROS sensitivity of cancer cells could also be attributed to depletion of the reduced thioredoxin (Trx-SH) pool caused by the inhibition of thioredoxin reductase 1 (TrxR1) by curcumin [76]. Indeed, Trx-SH and TRxR1 are key mediators in the maintenance of redox homeostasis of cells by maintaining a defense pool against oxidation [77].

5. Curcumin at the Crossroads between Autophagy, Necroptosis, and Apoptosis

In the following sections, we will try to depict the mechanistic aspects of curcumin-induced autophagy and apoptosis separately, occurring in the general context of a complex intracellular machinery dysregulation. This approach is somewhat absurd, but will facilitate the depiction of parallel signaling pathways all of which have their own thresholds regarding mitochondrial life, autophagy, cell cycle arrest, and cell death.

5.1. Curcumin, Autophagy, and Cell Death

Autophagy is the degradation process of supernumerary or dysfunctional components within cells. Any targeted cytosolic materials or organelles are ultimately delivered and recycled in lysosomes thus functioning as an important biological mechanism for cell homeostasis. As autophagy is such an ubiquitous and fundamental mechanism for the cell, autophagy dysfunction can be found in a number of diseases even if molecular evidences are still needed [78]. Autophagy in cancer diseases has attracted much attention to modulate cell death when targeted by therapeutic candidates like curcumin.

With the discovery and characterization of Atg proteins, the suppressive function of autophagy in cancer has been validated [79, 80]. Among the Atg genes, beclin 1 (Atg6) is an essential tumor suppressor that modulates the initiation and regulation of autophagy. BECN1 gene deletion is often present in human breast, ovarian, and prostate cancers, and aging Becn1+/- mice are prone to tumors including lymphomas and lung and liver cancers [8183]. The accumulation of autophagosomes in dying cells is correlated with autophagic cell death, also defined as a nonapoptotic form of programmed cell death (PCD) or type II PCD with a potential function of tumor suppression similar to apoptosis.

In addition to its tumor suppressive role, autophagy is involved in cancer cell survival under stress. For example, immortalized, apoptosis-defective, IL-3-dependent bone marrow cells deprived of growth factor show a better survival response when autophagy is induced. Accordingly, autophagy inhibition accelerates cell death [84, 85]. Other stressors like hormonal deprivation, chemotherapy, and radiation—in many cases—upregulate autophagy as a cell survival mechanism [86]. As this upregulation can be cell specific and modulates cell fate in a tissue, it may contribute to treatment resistance. In tumors, inflammation and lack of vasculature may often result in a decrease of glucose and oxygen levels. This perturbation in the tumor microenvironment, as well as acidosis, can induce autophagy. Autophagy is therefore a functional driver and a marker of cancer severity in clinical research [86, 87].

In this context, the anticancer activity of curcumin can be investigated. Curcumin acts also both as a tumor suppressor and cancer cell protector [8689].

The injection of curcumin in mice bearing breast cancer produces a clear inhibitory effect on the growth of breast cancer cells and metastasis [90].

Curcumin can inhibit the proliferation of tumor cells (Table 1) and induce the apoptosis of tumor cells (Figure 7), including bladder cancer [91], pancreatic cancer [92], prostate cancer [93], and uterine cervix carcinoma [94]. Curcumin also enhances the sensitivity to thermotherapy and γ-ray therapy [95, 96].


TargetEffectCancer typeRefs.

GRP78DownregulationColon[211]
EphA2DownregulationMelanoma[212]
SOCS1 and 3UpregulationLeukemia[213]
Nfr2DownregulationBreast[214]
MiR15a/16-1DownregulationLeukemia[215]
DCLE1UpregulationColon[216]
Skp2DownregulationGlioma[217]
FOXO1UpregulationPancreas[218]
EZH2DownregulationBreast[219]

In vitro, curcumin inhibits cell proliferation of chronic granulocyte leukemia (CGL), glioblastoma, and esophageal cancer through autophagy induction, by upregulating LC3-II and beclin 1, as well as accumulating autophagosomes. In contrast, with the autophagy inhibitor bafilomycin A1, curcumin-induced cell death is inhibited [97].

Curcumin can inhibit both PP1 and the Akt/p70S6K pathway to activate extracellular signal-regulated kinases (ERK1/2) and finally induce autophagy [98]. Besides activating autophagy, curcumin also exhibits time- or concentration-dependent inhibition of the growth of K562 cells.

Cell death induced by curcumin is correlated with the generation of autophagosomes, a drop of mitochondrial potential, and caspase activation [2, 3, 39]. In addition, curcumin reduces the expression of Bcl-2 protein in K562 cells [99]. A combined treatment of curcumin and adriamycin enhances the apoptosis of HepG2 cells by reducing the proportion of Bcl-2/Bax protein and caspase-3 activation, in parallel with an increase in autophagic flux and mitochondrial fission. These data may indicate that curcumin can increase adriamycin-induced toxicity by activating mitochondria-mediated autophagy [100].

5.2. Curcumin, ER-Mitochondria, and Apoptosis

The initial effects of curcumin could be due to its interaction with subcellular compartments since, as a lipophilic polyphenol, it could be associated with total lipophilic load and membranes. These subcellular compartments are essentially ER and the lysosomes [2, 3, 39], since oxidative stress [101104], lipid peroxidation [105], and calcium increase [106, 107] are associated with curcumin treatments and all these events are involved in the induction of cell death [102, 108] or specifically apoptosis [109111]. A plethora of recent papers brought evidence of curcumin binding to and/or inhibiting numerous proteins, i.e., Nrf2, β-catenin, NF-κB, inducible nitric oxide synthase, nitric oxide, amyloid plaques, ROS, cyclin D1, glutathione, cytosolic phospholipase A2, inhibitor of NF-κB kinase-1-2, P38MAPK, p-Tau (p-τ), and TNFα.

Most of the mechanisms by which curcumin exerts its anticancer effect have been reported to be related to cell death induction. Curcumin inhibits the inhibitor of κB kinase and IκBα phosphorylation [112115].

So, curcumin downregulates all genes downstream of NF-κB such as Bcl-2, Bcl-XL, cyclin D1, cyclin B1, matrix metalloproteinase-9, cyclooxygenase-2, and interleukin-6, resulting in cell cycle arrest (G2/M) (Figure 8) and induction of apoptosis [64, 112, 115117]. Also, curcumin exerts a strong inhibition resulting in a decreased cellular proliferation and induction of apoptosis that is mediated via the blockage of the Akt/mammalian target of rapamycin (mTOR) pathway and the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein [64, 118120]. Among the antitumor effects of curcumin are the downregulation of the transcription factors activator protein-1 [121125] and Egr-1 (Figure 8). Curcumin very potently reduces the cellular entry of viruses [126] and suppresses phorbol-ester-induced tumor promotion [127]. As curcumin can enter intracellular membranes and modify permeability and fluidity, it also acts on transporters and ion channels [128, 129]. Curcumin in association with the TORC1 and 2 inhibitors is thought to induce apoptosis via lysosome membrane permeabilization-associated autophagy [130].

-The curcumin capacity to induce an hormetic response is characterized by the numerous targets driving— depending on the dose —both antioxidant and prooxidant properties that can be related to the autophagic and cell death processes. The molecular circuits that link curcumin to cellular stress and death and how these pathways are uncoupled during hormetic responses are subjects of great interest [2, 3, 39]. Curcumin at very low concentrations (≤1 μM) behaves as an excellent antioxidant, but higher concentrations of curcumin (5–10 μM) operate primarily as an autophagy inducer, correlated with their capacity to reduce the acetylation of cytoplasmic proteins and cell cycle blockers (Figure 8).

Finally, at even higher concentrations—over 25 μM—autophagy fails to rescue cells and cell death is induced. We investigated the mechanistic aspects of the destabilization of ER and lysosomes involved in mitochondrially associated apoptosis. Curcumin induces an ER stress causing calcium release that in turn destabilizes the mitochondrial compartment to induce apoptosis. These events are also associated with lysosomal membrane permeabilization and activation of caspase-8, mediated by the activation of cathepsins and calpains [2, 3]. This complex interplay is of huge interest, as efficient autophagy may allow cells to escape the G2/M blockade [2] induced by curcumin when used at around 10-20 μM in the extracellular medium [3] (Figure 8).

5.3. Curcumin, Lysosomes, and Autophagy

As mentioned before, under physiological conditions, basal autophagy is a catabolic process where lysosomes are mainly involved in the degradation of damaged components and dysfunctional organelles in cells. Autophagy has attracted the interest of scientists in the field of cancer research because it is designated as an alternative programmed cell death (type II), whereas apoptosis is well known as programmed cell death type I [131]. But this definition has been modified and adapted to the discovery of multiple cell death pathways and of a diversity of autophagic processes.

We previously showed that a fraction of internalized curcumin is bound to the lysosomal membranes [2, 3] (Figure 4). Lysosomal destabilization by curcumin is critically dependent on the intracellular curcumin concentration; the occurrence of soluble lysosomal hydrolases, i.e., cathepsins and chemotrypsins; and the dysfunction of lysosomal-associated membrane proteins (LAMPs).

Growing evidence argues for the presence of highly activated PI3K/Akt signaling in cancer cells compared to normal ones. As we said earlier, curcumin inhibits the Akt-mTOR pathway and interferes with PI3K/Akt signaling, leading to the inhibition of the proliferation and reduction of the invasiveness and migration of various cancer cells, including triple-negative cancer cells [132135].

The Akt/mTOR/p70 ribosomal protein S6 kinase (p70S6K) and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathways are two major pathways that regulate autophagy induced during nutrient starvation. The Akt/mTOR/p70 and ERK1/2 pathways are frequently associated with oncogenesis in a variety of cancer cell types, including malignant gliomas. In U87-MG and U373-MG malignant glioma cells, curcumin induces G2/M arrest (Figure 8) and nonapoptotic autophagic cell death. It inhibits the Akt/mTOR/p70S6K pathway and activates the ERK1/2 pathway, thus inducing autophagy. It is interesting that the activation of the Akt pathway inhibits curcumin-induced autophagy and overall cytotoxicity, whereas the inhibition of the ERK1/2 pathway inhibits curcumin-induced autophagy and induces apoptosis, thus resulting in enhanced cytotoxicity. These results suggest that curcumin has high anticancer efficacy in vitro and in vivo by inducing autophagy [98].

Nevertheless, the effect of curcumin on lysosomes remains largely elusive. Some recent data suggest that currently known transcription factor EB (TFEB) activators are mainly inhibitors of mTOR which, as a master regulator of cell growth and metabolism, is involved in a wide range of biological functions [132137] and exerts its effect at the lysosomal membrane surface [137].

It has also been suggested that curcumin treatment may activate TFEB [138]. TFEB is a major player of the transcriptional response to starvation and controls autophagy by inducing lysosomal biogenesis, regulating autophagosome formation and autophagosome-lysosome fusion both in vitro and in vivo [139]. This is based on the cardinal hypothesis that a lysosome-to-nucleus signaling mechanism senses and regulates the lysosome via TFEB and mTOR [140]. Linked to lysosomal membranes, TFEB colocalizes with the master growth regulator mTOR complex 1 (mTORC1). The arguments for the fundamental role of TFEB are the following: curcumin binds directly to TFEB (and/or disturbs the membrane in the vicinity of TFEB insertion), promotes TFEB nuclear translocation, and increases the transcriptional activity of TFEB. TFEB modulators that act without inhibiting the mTOR pathway would probably be less deleterious to cells [141]. Along with this new argument, it has been reported that curcumin does not inhibit mTOR and fails to activate lysosomal function when constitutive activation of mTOR has been engineered, proving that curcumin-mediated lysosomal activation is achieved via suppression of mTOR activity. The AMPK-JNK pathway can also be activated by curcumin, which drives both mTOR inhibition and Bcl-2 upregulation and in turn enhanced autophagy and suppressed apoptosis [142]. Finally, inhibition of autophagic fluxes and activation/destabilization of the lysosomal compartment by curcumin, if passing a certain threshold, lead to more cell death, suggesting that lysosomal activation and enhanced autophagy serve—if successfully executed—as a cell survival mechanism to protect against curcumin-mediated cell death.

Taken together, all these data built up a novel insight into the regulatory mechanisms of curcumin at the lysosomal level (enhancing autophagy), which may reinforce the relevance of curcumin as a potential cancer therapeutic agent [138], but may also be used for lysosomal storage disorders, neurodegenerative disorders, and cardiovascular diseases.

6. Curcumin and Mitochondrial Turnover

6.1. Mitochondrial Biogenesis

Mitochondria are the key compartments of cellular energy metabolism that is also fundamental for apoptosis regulation and cell signaling. It is now established that the mitochondria of malignant cells differ structurally and functionally from those in normal cells and are mainly characterized by ROS overproduction, which may promote genomic instability by the alteration of gene expression and the modulation of signaling pathways. Both oxidative damages targeting the mitochondrial compartment and nuclear DNA induce further alterations of oxidative phosphorylation and enhance mitochondrial-specific ROS production, sustaining a “vicious cycle” between mitochondrial ROS, genomic instability, and cancer development. Alternatively, an impaired oxidative phosphorylation or mitochondrial biogenesis is found in neurodegenerative diseases [143145], cardiovascular diseases [146], and type II diabetes [147].

In this context, mitochondrial biogenesis—taken as the increase of the mitochondrial network—is a complex response to various stimuli that relies on both mitochondrial and nuclear genomes. Usually stimulated under supraenergetic demand, mitochondrial biogenesis involves a master regulator called peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) with peroxisome proliferator-activated receptor alpha (PPARα) activating nuclear respiratory factors 1 and 2 (NRF1/NRF2) among others [148]. Metabolic sensors like AMP-activated protein kinase (AMPK), NAD+/NADHH+ ratio, or ROS levels are first players of the PGC-1α pathway [149]. AMPK can modulate NAD+ levels in the cell contributing to [150] the activation of a NAD+-dependent deacetylase sirtuin 1 (SIRT1), which activates PGC-1α through deacetylation [151153]. Accordingly, high PGC-1α levels are found in tissues with high rates of oxidative phosphorylation, facing high ATP needs [154156]. Once activated, the AMPK/SIRT1/PGC-1α pathway involves NRF1 and NRF2 activating downstream of the estrogen-related receptor α (ERRα) and the expression of mitochondrial transcription factor A (TFAM) and transcription factors B1 and B2 (TFB1M and TFB2M) [157163]. These transcription factors are responsible for both the increased expression of nuclear DNA encoding for mitochondrial proteins [164] and the transcription/replication of mitochondrial DNA (mtDNA) [165167], thereby orchestrating mtDNA homeostasis at large [165, 168, 169].

In this context, the AMPK/SIRT1/PGC-1α pathway orchestrates mitochondrial biogenesis and participates in redox homeostasis, crucial for cell life (Figure 9).

Studies describing curcumin as an enhancer of mitochondrial biogenesis are quite recent and should point to a new path for curcumin studies, as a kick-start to develop newly designed drugs that target dysfunctional mitochondria found in cardiovascular diseases and neurodegeneration.

However, the external concentrations of curcumin used in experimental models discussed here are high and may not be reached in the human system through food or oral medication. As mentioned before [2, 3], it will be necessary to improve curcumin bioavailability, to ensure that higher curcumin concentrations can be reached, or to find a way to address curcumin to target cells. This explains why curcumin is becoming a common model in biotechnology and drug delivery studies seeking better permeability and stability [170] as well as new nanoformulations [170172].

In vitro, curcumin has been described as a potent inducer of a brown fat-like phenotype in 3T3-L1 and primary white adipocytes [173].

In these cells, 20 μM curcumin for 6 days upregulates PGC-1α, associated with an increased level of cytochrome c, the phosphorylated form of AMPK (p-AMPK), Nrf1, TFAM1, and the total mtDNA transcript.

In gentamicin-treated LLC-PK1 cells, 30 μM of curcumin for 24 h induces Nrf2 translocation and upregulates PGC-1α. This evidence shows that curcumin can elicit mitochondrial biogenesis in vitro via Nrf2 as a master regulator of the redox cellular environment [174, 175].

More in vivo studies are in line with these data and show that curcumin can upregulate respiratory chain components. In gastrocnemius and soleus muscles of rats submitted to long-lasting exercise training, curcumin induces an increase in the amounts of cytochrome c oxidase and various subunits of complexes I, II, and III [176]. Curcumin also stimulates the effects of exercise training upon mtDNA synthesis and citrate synthase (CS) activity which are the gold standards for evaluating mitochondrial biogenesis in muscles. As curcumin can modulate AMP and NAD+ levels, it can thereby activate AMPK and all downstream players of the AMPK/SIRT1/PGC-1α. Rats submitted to ischemic reperfusion injury after curcumin pretreatment exhibited a better developed mitochondrial network in the cerebral cortex [177]. Curcumin pretreatment prevented the injury-induced downregulation of uncoupling protein 2 (UCP2),Nrf1 levels. and TFAM which were upregulated at all concentrations tested. Curcumin (400 mg/kg day−1) provided by gavage prior to gentamicin (a renal toxin) exposure preserved mitochondrial morphology and enhanced the number of mitochondria [175].

In mice, curcumin also demonstrated the browning of white adipose tissue by UCP1 and PGC-1α upregulation, with an increase of mtDNA transcripts [178].

All these findings reinforce the new hypothesis that curcumin at very low concentrations may induce mitochondrial biogenesis, but new data on the impact of curcumin on regulators of mitochondrial biogenesis, such as AMPK, SIRT1, NRF1, and TFAM, will be of great interest.

6.2. Curcumin and Mitophagy

It is now established that a fine regulation balancing mitochondrial biogenesis and mitophagy is essential to maintain the adaptability of the cell to its metabolic state, intracellular stress, and environmental signals [179].

Regulatory factors contributing to mitochondrial homeostasis have also been linked to carcinogenesis, which points at mitophagy as a potential target for cancer therapy [180].

Mitophagy is the process by which damaged mitochondria are removed from the cells through engulfment by an active autophagosome in a PTEN-induced kinase 1 (PINK1)/Parkin (E3 ubiquitin ligase)-dependent mechanism [181183]. Despite being a physiological process, increased rates of mitophagy have been found in some human diseases and may represent a major risk for redox and bioenergetic homeostasis [184187].

The capacity of curcumin to induce mitochondrial biogenesis (certainly at low concentrations) in response to enhanced energetic demand is followed by curcumin’s potential to trigger mitophagy [2, 3, 188], and once again the threshold concept is of most relevance.

CNE2 cells (nasopharyngeal carcinoma) can be sensitized with 10 μM curcumin before being exposed to ultrasound [189]. A combination of ultrasound and curcumin increases the number of swollen mitochondria and impairs mitochondrial membrane architecture. These results constitute some evidence that altered mitochondria could be eliminated by specific autophagy in response to curcumin. Nevertheless, more data are needed to elucidate if curcumin is a general inducer of autophagy or contributes specifically to a mitophagic process.

Additional data are needed to elucidate the exact role of curcumin as an inducer of mitophagy. The scenario in which curcumin would be useful in inducing mitochondrial degradation requires more detail.

7. Curcumin and Regulatory MicroRNA

In cancer research, microRNAs (miRs) have attracted much attention as one therapeutic agent could physiologically regulate multiple targets to limit cancer progression. However, as multiple pathways are involved with hundreds of miRs, this approach is still challenging. Recent studies revealed that curcumin can regulate miRs, and one strategy may be to investigate miRs through curcumin multitargeting.

MicroRNA-21 (miR-21) can be taken as a model for studying regulatory mechanisms between microRNA and curcumin [190, 191]. miR-21 is involved in proliferation, apoptosis, metastasis, and anticancer drug resistance. miR-21 is also involved in several downstream pathways, such as phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase, protein kinase B (PI3K/Akt), programmed cell death protein 4 (PCD4), and MAPK pathways, and in the enhancement of p53 and NF-κB pathways. It is interesting to note that all these pathways have been described as being affected by curcumin cellular loading. Curcumin decreases miR-21 levels by both increasing the miR-21 exosome outside the cells and by binding to its promoter, a situation that decreases the transcription of the miR-21 gene.

Beyond miR-21 inhibition, curcumin induces epigenetic alterations by modulating the expression of several other oncogenic and tumor suppressor miRs (Table 2). Suppression of oncomiRs such as miR-21, miR-17-5p, miR-20a, miR-27a, and miR-186 [191] and overexpression of miR-34 and epithelial-mesenchymal-transition suppressor miRs are among the most important effects of curcumin [192]. A recent publication highlights curcumin as a relevant miR regulator for cancer progression and points out that exosomes produced in curcumin-treated cells contain both miRs and curcumin and carry anticancer properties for the recipient cells [193]. This mechanism of physiological vectorization of curcumin, by curcumin or not, may open a new approach to investigate for potential therapeutic tools in cancer therapy.


Cancer originUpregulatedDownregulatedTargetsRefs.

PancreasmiR-22miR-21SP1, ESR1[220]
miR-200miR-199aPTEN[221]
ColorectummiR-21AP1, Pdcd4[222]
BreastmiR-15aBcl-2[223]
miR-16
Lungmir-206PI3K/AKT/mTOR[224]
LungmiR-186Caspase-10[191]
RetinoblastomemiR-99aJAK/STAT[225]
Thymic carcinomamiR-27aNotch1/mTOR[226]
OsteosarcomamiR-21RECK[227]
RetinoblastomemiR-22Erbb3[228]

Additionally, curcumin regulates many other miRNA expressions, e.g., miR-1, miR-7, miR-9, miR-19, miR-34a, and miR-181 [193].

8. Curcumin: PAINS or Nutraceutical?

As previously discussed, curcumin has been attracting massive attention, particularly over the last decade, not only for its use as a chemotherapeutic agent but also for its antioxidant properties. It has several advertising advantages: a natural product already used in Ayurvedic medicine, easily extractible from plants (turmeric), rather inexpensive, and with beneficial effects when included in the diet, the latter observation being initially supported by epidemiological studies. Its pleiotropic effects as evidenced in numerous studies attracted the attention of scientists and lay people drawn to natural products now labeled as “superfoods.”

On the other hand, some researchers raised concerns about curcumin and other natural products classifying them as Pan Assay Interference Compounds (PAINS) [194].

Typically, it does not behave in a drug-like manner with its target, a behavior potentially unspecific, unquantifiable, and interfering with assays measuring them or other readouts. Warnings come from the drug discovery field, in high-throughput screening (HTS) where these PAINS largely return as “hits” for a considered target. Of course, anyone actively involved in high-throughput screening (HTS) should consider the latest considerations regarding PAINS to filter their hits [195]. In fact, HTS experts working with biologists know that it is considered a rather uncertain research often leading to multiple “hits”, hitting themselves multiple targets [196].

Medicinal chemists warned us about curcumin’s status not only as a PAINS but also as an AIC (assay interference compound) and an IMP (invalid/improbable metabolic panacea) status) [197] which has led to divisions within the scientific community [198, 199]. The complexity of curcumin’s behavior should reinforce our interest to discuss the best way to design our tests and readouts. In this review, we point out the hormetic behavior of curcumin and its ability to hit multiple pathways, and not only proteins but also membranes. What could be a “no go” to researchers following the perspective of one drug and one protein with one active site can be put in perspective of the advantages of modulating a balance of pathways and doing some, what researchers call, multitargeting [200].

To circumvent some of the limitations of natural products like poor solubility and bioavailability, researchers vectorize them with nanomaterials. A literature search will show that curcumin and nanoparticles return hundreds of studies, and more than half of them have applications for cancer; the rest are comprised of applications for inflammation and vascular diseases.

It would need a complete separate review to cover curcumin and its nanoformulations, but the therapeutic use of natural products could benefit from research in nanomedicine as some of the latest nanoformulations are using targeting moieties that are tissue- and cell-specific [201, 202]. Such nanoformulations could alleviate most of the systemic limitations of curcumin and bring that “multitargeting drug” at the cellular level.

9. Conclusion

Although some fourteen thousand publications contain the term curcumin, few studies have followed new research directions. It is clear that low levels of curcumin enhance mitochondrial biogenesis in cells and tissues, mainly through the induction of the PGC-1α-related signaling pathway [203, 204]. The exact mechanism of curcumin-induced mitochondrial biogenesis is incompletely understood, since the roles of AMPK, NRF1, Nfr2, and/or TFAM that are essential in biological processes were not investigated in most published studies. It is sure that TFEB is also involved in such pathway, participating in lysosomal biogenesis together with autophagy induction [138]. Molecules such as PGC-1α are thought to be critical for the maintenance of organelle content. The hypothesis that the induction of mitochondrial biogenesis by exogenous polyphenols may play a role in alleviating cellular dysfunction with the disruption of mitochondrial bioenergetics, in cases of neurodegenerative and cardiovascular diseases, is of great value, even though our knowledge of curcumin-mediated regulation of mitochondrial biogenesis is limited [165, 166, 168].

Investigations of the role of curcumin as an inducer of mitochondrial biogenesis and mitophagy in a context of mitochondrial energetic disturbance are in their infancy. By focusing efforts on TFEB, a protein widely considered to be the most important regulator of autophagy and lysosomal biogenesis, we may perhaps shed light on the regulation of mitophagy in various cell types.

Curcumin induces crosstalk between apoptosis and autophagy and is thought to interact with proteins that belong to both pathways and are involved in the regulation of cancer cell death. Most researchers consider that cancer progression is in large part due to defects in cell death mechanisms [205, 206]. These defects shield tumor cells from drugs and therapies, thus prolonging cell life and promoting cell dispersion. Autophagy and apoptosis are safeguards against cellular damages and uncontrolled outgrowth and differentiation of harmful cells. Autophagic proteins generally hinder apoptosis, whereas apoptotic intermediates prevent autophagic responses. Additionally, curcumin analogs have been described with attenuating properties on AD accumulation in a mouse model of Alzheimer’s disease [207]. This effect is mediated by a reduced level of amyloid-β protein associated with enhanced autophagy.

The case of curcumin, autophagy, and apoptosis, which are highly intricate pathways (Figure 10), can be investigated by manipulating their mutual proteins. Targeting these shared proteins involved in the crosstalk between autophagy and apoptosis so as to regulate tumor cell death is crucial for the successful design of future anticancer therapies. MicroRNAs are involved in the modulation of these components that interact in both autophagy and apoptosis in cancer cells. Since the development of miRNA-based therapeutics seems to be hazardous and time-consuming, additional approaches need to be considered. Curcumin as a phytochemical may fill this gap since it has been reported to switch these interplaying proteins to maximize cancer cell death through the partnership of autophagy and apoptosis [2, 39, 138]. This may enable us to chart the missing links between these machinery proteins, organelle membranes, and miRNAs.

Beyond curcumin, knowledge of the role of natural chemopreventive agents in autophagy and apoptosis will certainly expand [208] and may lead to anticancer therapies with minimal adverse effects [209]. The study of the role of natural agents that induce beneficial cross-talk between apoptosis and autophagy to finely tune cell death is also at the forefront of new therapeutic discoveries in metabolic disorders and aging.

Abbreviations

AP1:Activator protein 1 (AP-1), a transcription factor
Caspase-10:Cleaves and activates caspase-3 and caspase-7, and the protein itself is processed by caspase-8
EphA2:EPH receptor A2 (ephrin type-A receptor 2) is a protein encoded by the EPHA2 gene and belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family
EZH2:Enhancer of zeste homolog 2 is a histone-lysine N-methyltransferase enzyme (EC 2.1.1.43) encoded by the EZH2 gene which participates in DNA methylation and transcriptional repression
ESR1:Estrogen receptor 1
FOXO1:Forkhead box protein O1, also known as forkhead in rhabdomyosarcoma, is a protein that in humans is encoded by the FOXO1 gene
GRP78:Member of the HSP family of molecular chaperones required for endoplasmic reticulum integrity and stress-induced autophagy
Nfr2:Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2, is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation
Pcdc4:Programmed cell death protein 4 target of the oncomiR miR-21
PTEN:Gene that was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency
Skp2:S-phase kinase-associated protein 2
SOCS1 and SOCS3:Genes that encode members of the STAT-induced STAT inhibitor family (SSI), also known as suppressors of cytokine signaling (SOCS)
SP1:Protein encoded by this gene is a zinc finger transcription factor that binds to GC-rich motifs of many promoters.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

Patrice X. Petit, Nathan E. Rainey, and Aoula Moustapha have equally contributed to the redaction of this article. Nathan E. Rainey and Aoula Moustapha both produce a PhD thesis related to this topic in December 2019 and 2015, respectively, and authored some important articles in the field of curcumin chemistry and functional physiology that have been published in international journals.

Acknowledgments

This work was funded with basic support from both the “Centre National de la Recherche Scientifique” (CNRS) and the “Institut National de La Santé et de la Recherche Medicale” (INSERM) to Patrice X. Petit. Nathan E. Rainey is supported by a PhD grant from “Université Sorbonne Paris Cité.” AFM (Association Française contre les Myopathies, grants 15137 and 15661) funding was also used for this work. We also thank Raphael Parker (Paris University) for his intervention on an early assessment of the manuscript.

References

  1. K. Priyadarsini, “The chemistry of curcumin: from extraction to therapeutic agent,” Molecules, vol. 19, no. 12, pp. 20091–20112, 2014. View at: Publisher Site | Google Scholar
  2. A. Moustapha, P. A. Pérétout, N. E. Rainey et al., “Curcumin induces crosstalk between autophagy and apoptosis mediated by calcium release from the endoplasmic reticulum, lysosomal destabilization and mitochondrial events,” Cell Death Discovery, vol. 1, no. 1, 2015. View at: Publisher Site | Google Scholar
  3. F. J. Sala de Oyanguren, N. E. Rainey, A. Moustapha et al., “Highlighting curcumin-induced crosstalk between autophagy and apoptosis as supported by its specific subcellular localization,” Cell, vol. 9, no. 2, p. 361, 2020. View at: Publisher Site | Google Scholar
  4. V. Lampe and J. Milobedzka, “Studien über curcumin,” Berichte der Deutschen Chemischen Gesellschaft, vol. 46, no. 2, pp. 2235–2240, 1913. View at: Publisher Site | Google Scholar
  5. H. J. J. Pabon, “A Synthesis of curcumin and related compounds,” Recueil des Travaux Chimiques des Pays-Bas, vol. 83, no. 4, pp. 379–386, 1964. View at: Publisher Site | Google Scholar
  6. K. V. D. Babu and K. N. Rajasekharan, “Simplified condition for synthesis of curcumin I and other curcuminoids,” Organic Preparations and Procedures International, vol. 26, no. 6, pp. 674–677, 1994. View at: Publisher Site | Google Scholar
  7. E. V. Rao, Y. R. Prasad, and P. Sudheer, “Revisiting curcumin Chemistry- part II: synthesis of Monomethylcurcumin and Isomeric Demethoxycurcumins and their Characterization,” Indian Journal of Pharmaceutical Sciences, vol. 79, no. 5, 2017. View at: Publisher Site | Google Scholar
  8. S. Venkateswarlu, M. S. Ramachandra, and G. V. Subbaraju, “Synthesis and biological evaluation of polyhydroxycurcuminoids,” Bioorganic & Medicinal Chemistry, vol. 13, no. 23, pp. 6374–6380, 2005. View at: Publisher Site | Google Scholar
  9. I. Ali, A. Haque, and K. Saleem, “Separation and identification of curcuminoids in turmeric powder by HPLC using phenyl column,” Analytical Methods, vol. 6, no. 8, pp. 2526–2536, 2014. View at: Publisher Site | Google Scholar
  10. K. J. Lee, Y. S. Kim, and J. Y. Ma, “Separation and identification of curcuminoids from Asian turmeric (Curcuma longa L.) using RP-HPLC and LC-MS,” Asian Journal of Chemistry, vol. 25, no. 2, pp. 909–912, 2013. View at: Publisher Site | Google Scholar
  11. O. P. Sharma, “Antioxidant activity of curcumin and related compounds,” Biochemical Pharmacology, vol. 25, no. 15, pp. 1811-1812, 1976. View at: Publisher Site | Google Scholar
  12. K. I. Priyadarsini, “Photophysics, photochemistry and photobiology of curcumin: studies from organic solutions, bio-mimetics and living cells,” Journal of Photochemistry and Photobiology C, vol. 10, no. 2, pp. 81–95, 2009. View at: Publisher Site | Google Scholar
  13. K. Mohammadi, K. H. Thompson, B. O. Patrick et al., “Synthesis and characterization of dual function vanadyl, gallium and indium curcumin complexes for medicinal applications,” Journal of Inorganic Biochemistry, vol. 99, no. 11, pp. 2217–2225, 2005. View at: Publisher Site | Google Scholar
  14. A. Barik, B. Mishra, L. Shen et al., “Evaluation of a new copper(II)-curcumin complex as superoxide dismutase mimic and its free radical reactions,” Free Radical Biology & Medicine, vol. 39, no. 6, pp. 811–822, 2005. View at: Publisher Site | Google Scholar
  15. P. R. Koiram, V. P. Veerapur, A. Kunwar et al., “Effect of curcumin and curcumin copper complex (1 : 1) on radiation-induced changes of anti-oxidant enzymes levels in the livers of Swiss albino mice,” Journal of Radiation Research, vol. 48, no. 3, pp. 241–245, 2007. View at: Publisher Site | Google Scholar
  16. O. Vajragupta, P. Boonchoong, and L. J. Berliner, “Manganese complexes of curcumin analogues: evaluation of hydroxyl radical scavenging ability, superoxide dismutase activity and stability towards hydrolysis,” Free Radical Research, vol. 38, no. 3, pp. 303–314, 2009. View at: Publisher Site | Google Scholar
  17. A. Kunwar, H. Narang, K. I. Priyadarsini, M. Krishna, R. Pandey, and K. B. Sainis, “Delayed activation of PKCδ and NFκB and higher radioprotection in splenic lymphocytes by copper (II)-curcumin (1:1) complex as compared to curcumin,” Journal of Cellular Biochemistry, vol. 102, no. 5, pp. 1214–1224, 2007. View at: Publisher Site | Google Scholar
  18. L. Baum and A. Ng, “Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer’s disease animal models,” Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 367–377, 2004. View at: Publisher Site | Google Scholar
  19. T. Jiang, X. L. Zhi, Y. H. Zhang, L. F. Pan, and P. Zhou, “Inhibitory effect of curcumin on the Al(III)-induced Aβ42 aggregation and neurotoxicity in vitro,” Biochimica et Biophysica Acta, vol. 1822, no. 8, pp. 1207–1215, 2012. View at: Publisher Site | Google Scholar
  20. N. E. Rainey, A. Moustapha, A. Saric, G. Nicolas, F. Sureau, and P. X. Petit, “Iron chelation by curcumin suppresses both curcumin-induced autophagy and cell death together with iron overload neoplastic transformation,” Cell Death Discovery, vol. 5, no. 1, 2019. View at: Publisher Site | Google Scholar
  21. G. J. Szebeni, Á. Balázs, I. Madarász et al., “Achiral Mannich-base curcumin analogs induce unfolded protein response and mitochondrial membrane depolarization in PANC-1 cells,” International Journal of Molecular Sciences, vol. 18, no. 10, p. 2105, 2017. View at: Publisher Site | Google Scholar
  22. M. Asti, E. Ferrari, S. Croci et al., “Synthesis and characterization of (68) Ga-labeled curcumin and curcuminoid complexes as potential radiotracers for imaging of cancer and Alzheimer’s disease,” Inorganic Chemistry, vol. 53, no. 10, pp. 4922–4933, 2014. View at: Publisher Site | Google Scholar
  23. E. Ferrari, M. Asti, R. Benassi, F. Pignedoli, and M. Saladini, “Metal binding ability of curcumin derivatives: a theoretical vs. experimental approach,” Dalton Transactions, vol. 42, no. 15, pp. 5304–5313, 2013. View at: Publisher Site | Google Scholar
  24. M. I. Khalil, A. M. Al-Zahem, and M. H. Al-Qunaibit, “Synthesis, Characterization, Mössbauer Parameters, and Antitumor Activity of Fe(III) Curcumin Complex,” Bioinorganic Chemistry and Applications, vol. 2013, 5 pages, 2013. View at: Publisher Site | Google Scholar
  25. H. Oguzturk, O. Ciftci, M. Aydin, N. Timurkaan, A. Beytur, and F. Yilmaz, “Ameliorative effects of curcumin against acute cadmium toxicity on male reproductive system in rats,” Andrologia, vol. 44, no. 4, pp. 243–249, 2012. View at: Publisher Site | Google Scholar
  26. R. Pallikkavil, M. B. Ummathur, S. Sreedharan, and K. Krishnankutty, “Synthesis, characterization and antimicrobial studies of Cd(II), Hg(II), Pb(II), Sn(II) and Ca(II) complexes of curcumin,” Main Group Metal Chemistry, vol. 36, no. 3-4, pp. 123–127, 2013. View at: Publisher Site | Google Scholar
  27. A. Valentini, F. Conforti, A. Crispini et al., “Synthesis, oxidant properties, and antitumoral effects of a heteroleptic palladium(II) complex of curcumin on human prostate cancer cells,” Journal of Medicinal Chemistry, vol. 52, no. 2, pp. 484–491, 2009. View at: Publisher Site | Google Scholar
  28. T. Ak and I. Gulcin, “Antioxidant and radical scavenging properties of curcumin,” Chemico-Biological Interactions, vol. 174, no. 1, pp. 27–37, 2008. View at: Publisher Site | Google Scholar
  29. M. Borsari, E. Ferrari, R. Grandi, and M. Saladini, “Curcuminoids as potential new iron-chelating agents: spectroscopic, polarographic and potentiometric study on their Fe(III) complexing ability,” Inorganic Chemistry Acta, vol. 328, no. 1, pp. 61–68, 2002. View at: Publisher Site | Google Scholar
  30. Y. Jiao, J. Wilkinson IV, E. Christine Pietsch et al., “Iron chelation in the biological activity of curcumin,” Free Radical Biology and Medicine, vol. 40, no. 7, pp. 1152–1160, 2006. View at: Publisher Site | Google Scholar
  31. A. Barik, B. Mishra, A. Kunwar et al., “Comparative study of copper(II)-curcumin complexes as superoxide dismutase mimics and free radical scavengers,” European Journal of Medicinal Chemistry, vol. 42, no. 4, pp. 431–439, 2007. View at: Publisher Site | Google Scholar
  32. K. I. Priyadarsini, “Chemical and structural features influencing the biological activity of curcumin,” Current Pharmaceutical Design, vol. 19, no. 11, pp. 2093–2100, 2013. View at: Publisher Site | Google Scholar
  33. S. Wanninger, V. Lorenz, A. Subhan, and F. T. Edelmann, “Metal complexes of curcumin—synthetic strategies, structures and medicinal applications,” Chemical Society Reviews, vol. 44, no. 15, pp. 4986–5002, 2015. View at: Publisher Site | Google Scholar
  34. A. Goel and B. B. Aggarwal, “Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs,” Nutrition and Cancer, vol. 62, no. 7, pp. 919–930, 2010. View at: Publisher Site | Google Scholar
  35. S. C. Gupta, B. Sung, J. H. Kim, S. Prasad, S. Li, and B. B. Aggarwal, “Multitargeting by turmeric, the golden spice: from kitchen to clinic,” Molecular Nutrition & Food Research, vol. 57, no. 9, pp. 1510–1528, 2013. View at: Publisher Site | Google Scholar
  36. D. J. Messner, T. Robinson, and K. V. Kowdley, “Curcumin and turmeric modulate the tumor-promoting effects of iron in vitro,” Nutrition and Cancer, vol. 69, no. 3, pp. 481–489, 2017. View at: Publisher Site | Google Scholar
  37. S. Prasad, S. C. Gupta, A. K. Tyagi, and B. B. Aggarwal, “Curcumin, a component of golden spice: from bedside to bench and back,” Biotechnology Advances, vol. 32, no. 6, pp. 1053–1064, 2014. View at: Publisher Site | Google Scholar
  38. S. Prasad, A. K. Tyagi, and B. B. Aggarwal, “Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: the golden pigment from golden spice,” Cancer Research and Treatment, vol. 46, no. 1, pp. 2–18, 2014. View at: Publisher Site | Google Scholar
  39. N. Rainey, L. Motte, B. B. Aggarwal, and P. X. Petit, “Curcumin hormesis mediates a cross-talk between autophagy and cell death,” Cell Death & Disease, vol. 6, no. 12, p. e2003, 2015. View at: Publisher Site | Google Scholar
  40. M. H. Leung, T. Harada, and T. W. Kee, “Delivery of curcumin and medicinal effects of the copper(II)-curcumin complexes,” Current Pharmaceutical Design, vol. 19, no. 11, pp. 2070–2083, 2013. View at: Publisher Site | Google Scholar
  41. O. Vajragupta, P. Boonchoong, H. Watanabe, M. Tohda, N. Kummasud, and Y. Sumanont, “Manganese complexes of curcumin and its derivatives: evaluation for the radical scavenging ability and neuroprotective activity,” Free Radical Biology & Medicine, vol. 35, no. 12, pp. 1632–1644, 2003. View at: Publisher Site | Google Scholar
  42. T. Jiang, L. Wang, S. Zhang et al., “Interaction of curcumin with Al(III) and its complex structures based on experiments and theoretical calculations,” Journal of Molecular Structure, vol. 1004, no. 1-3, pp. 163–173, 2011. View at: Publisher Site | Google Scholar
  43. M. Gianluca, F. Erika, L. Gigliola et al., “The role of coordination chemistry in the development of innovative gallium-based bioceramics: the case of curcumin,” Journal of Materials Chemistry, vol. 21, no. 13, p. 5027, 2011. View at: Publisher Site | Google Scholar
  44. X. Mei, D. Xu, S. Xu, Y. Zheng, and S. Xu, “Gastroprotective and antidepressant effects of a new zinc(II)-curcumin complex in rodent models of gastric ulcer and depression induced by stresses,” Pharmacology, Biochemistry, and Behavior, vol. 99, no. 1, pp. 66–74, 2011. View at: Publisher Site | Google Scholar
  45. D. Pucci, T. Bellini, A. Crispini et al., “DNA binding and cytotoxicity of fluorescent curcumin-based Zn(II) complexes,” Medicinal Chemistry Communications, vol. 3, no. 4, p. 462, 2012. View at: Publisher Site | Google Scholar
  46. K. K. Sharma, S. Chandra, and D. K. Basu, “Synthesis and antiarthritic study of a new orally active diferuloyl methane (curcumin) gold complex,” Inorganica Chimica Acta, vol. 135, no. 1, pp. 47-48, 1987. View at: Publisher Site | Google Scholar
  47. K. H. Thompson, K. Bohmerle, E. Polishchuk et al., “Complementary inhibition of synoviocyte, smooth muscle cell or mouse lymphoma cell proliferation by a vanadyl curcumin complex compared to curcumin alone,” Journal of Inorganic Biochemistry, vol. 98, no. 12, pp. 2063–2070, 2004. View at: Publisher Site | Google Scholar
  48. R. Agarwal, S. K. Goel, and J. R. Behari, “Detoxification and antioxidant effects of curcumin in rats experimentally exposed to mercury,” Journal of Applied Toxicology, vol. 30, no. 5, pp. 457–468, 2010. View at: Publisher Site | Google Scholar
  49. S. Daniel, J. L. Limson, A. Dairam, G. M. Watkins, and S. Daya, “Through metal binding, curcumin protects against lead- and cadmium-induced lipid peroxidation in rat brain homogenates and against lead-induced tissue damage in rat brain,” Journal of Inorganic Biochemistry, vol. 98, no. 2, pp. 266–275, 2004. View at: Publisher Site | Google Scholar
  50. V. Eybl, D. Kotyzová, L. Lešetický, M. Bludovská, and J. Koutenský, “The influence of curcumin and manganese complex of curcumin on cadmium-induced oxidative damage and trace elements status in tissues of mice,” Journal of Applied Toxicology, vol. 26, no. 3, pp. 207–212, 2006. View at: Publisher Site | Google Scholar
  51. J. Rennolds, S. Malireddy, F. Hassan et al., “Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium,” Biochemical and Biophysical Research Communications, vol. 417, no. 1, pp. 256–261, 2012. View at: Publisher Site | Google Scholar
  52. M. O. Iwunze and D. McEwan, “Peroxynitrite interaction with curcumin solubilized in ethanolic solution,” Cellular and Molecular Biology (Noisy-le-Grand, France), vol. 50, pp. 749–752, 2004. View at: Google Scholar
  53. S. V. Jovanovic, C. W. Boone, S. Steenken, M. Trinoga, and R. B. Kaskey, “How curcumin works preferentially with water soluble antioxidants,” Journal of the American Chemical Society, vol. 123, no. 13, pp. 3064–3068, 2001. View at: Publisher Site | Google Scholar
  54. J. E. Kim, A. R. Kim, H. Y. Chung, S. Y. Han, B. S. Kim, and J. S. Choi, “In vitro peroxynitrite scavenging activity of diarylheptanoids from Curcuma longa,” Phytotherapy Research, vol. 17, no. 5, pp. 481–484, 2003. View at: Publisher Site | Google Scholar
  55. B. Mishra, K. I. Priyadarsini, M. K. Bhide, R. M. Kadam, and H. Mohan, “Reactions of superoxide radicals with curcumin: probable mechanisms by optical spectroscopy and EPR,” Free Radical Research, vol. 38, no. 4, pp. 355–362, 2009. View at: Publisher Site | Google Scholar
  56. K. I. Priyadarsini, “Free radical reactions of curcumin in membrane models,” Free Radical Biology & Medicine, vol. 23, no. 6, pp. 838–843, 1997. View at: Publisher Site | Google Scholar
  57. K. I. Priyadarsini, D. K. Maity, G. H. Naik et al., “Role of phenolic O-H and methylene hydrogen on the free radical reactions and antioxidant activity of curcumin,” Free Radical Biology & Medicine, vol. 35, no. 5, pp. 475–484, 2003. View at: Publisher Site | Google Scholar
  58. Y. M. Sun, H. Y. Zhang, D. Z. Chen, and C. B. Liu, “Theoretical elucidation on the antioxidant mechanism of curcumin: a DFT study,” Organic Letters, vol. 4, no. 17, pp. 2909–2911, 2002. View at: Publisher Site | Google Scholar
  59. M. Roy and S. Mukherjee, “Reversal of resistance towards cisplatin by curcumin in cervical cancer cells,” Asian Pacific Journal of Cancer Prevention, vol. 15, no. 3, pp. 1403–1410, 2014. View at: Publisher Site | Google Scholar
  60. M. T. Kuo, “Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities,” Antioxidants & Redox Signaling, vol. 11, no. 1, pp. 99–133, 2009. View at: Publisher Site | Google Scholar
  61. W. Song, R. Jiang, and C. M. Zhao, “Role of integrin-linked kinase in multi-drug resistance of human gastric carcinoma SGC7901/DDP cells,” Asian Pacific Journal of Cancer Prevention, vol. 13, no. 11, pp. 5619–5625, 2012. View at: Publisher Site | Google Scholar
  62. C. N. Sreekanth, S. V. Bava, E. Sreekumar, and R. J. Anto, “Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer,” Oncogene, vol. 30, no. 28, pp. 3139–3152, 2011. View at: Publisher Site | Google Scholar
  63. P. Javvadi, A. T. Segan, S. W. Tuttle, and C. Koumenis, “The chemopreventive agent curcumin is a potent radiosensitizer of human cervical tumor cells via increased reactive oxygen species production and overactivation of the mitogen-activated protein kinase pathway,” Molecular Pharmacology, vol. 73, no. 5, pp. 1491–1501, 2008. View at: Publisher Site | Google Scholar
  64. B. B. Aggarwal, S. Shishodia, Y. Takada et al., “Curcumin suppresses the paclitaxel-induced nuclear factor-κB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice,” Clinical Cancer Research, vol. 11, no. 20, pp. 7490–7498, 2005. View at: Publisher Site | Google Scholar
  65. Y. P. Dang, X. Y. Yuan, R. Tian, D. G. Li, and W. Liu, “Curcumin improves the paclitaxel-induced apoptosis of HPV-positive human cervical cancer cells via the NF-κB-p53-caspase-3 pathway,” Experimental and Therapeutic Medicine, vol. 9, no. 4, pp. 1470–1476, 2015. View at: Publisher Site | Google Scholar
  66. P. Anand, S. G. Thomas, A. B. Kunnumakkara et al., “Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature,” Biochemical Pharmacology, vol. 76, no. 11, pp. 1590–1611, 2008. View at: Publisher Site | Google Scholar
  67. K. S. Bhullar, A. Jha, and H. P. V. Rupasinghe, “Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells,” Chemico-Biological Interactions, vol. 242, pp. 107–122, 2015. View at: Publisher Site | Google Scholar
  68. H. Gali-Muhtasib, R. Hmadi, M. Kareh, R. Tohme, and N. Darwiche, “Cell death mechanisms of plant-derived anticancer drugs: beyond apoptosis,” Apoptosis, vol. 20, no. 12, pp. 1531–1562, 2015. View at: Publisher Site | Google Scholar
  69. M. Hosseinzadehdehkordi, A. Adelinik, and A. Tashakor, “Dual effect of curcumin targets reactive oxygen species, adenosine triphosphate contents and intermediate steps of mitochondria-mediated apoptosis in lung cancer cell lines,” European Journal of Pharmacology, vol. 769, pp. 203–210, 2015. View at: Publisher Site | Google Scholar
  70. J. Sun, Y. Zhao, H. Jin, and J. Hu, “Curcumin relieves TPA-induced Th1 inflammation in K14-VEGF transgenic mice,” International Immunopharmacology, vol. 25, no. 2, pp. 235–241, 2015. View at: Publisher Site | Google Scholar
  71. G. Weng, Y. Zeng, J. Huang, J. Fan, and K. Guo, “Curcumin enhanced busulfan-induced apoptosis through downregulating the expression of survivin in leukemia stem-like KG1a cells,” BioMed Research International, vol. 2015, Article ID 630397, 16 pages, 2015. View at: Publisher Site | Google Scholar
  72. O. J. F. Banji, D. Banji, and K. Ch, “Curcumin and hesperidin improve cognition by suppressing mitochondrial dysfunction and apoptosis induced by D-galactose in rat brain,” Food and Chemical Toxicology, vol. 74, pp. 51–59, 2014. View at: Publisher Site | Google Scholar
  73. A. Priyanka, S. S. Anusree, V. M. Nisha, and K. G. Raghu, “Curcumin improves hypoxia induced dysfunctions in 3T3-L1 adipocytes by protecting mitochondria and down regulating inflammation,” Biofactors, vol. 40, no. 5, pp. 513–523, 2014. View at: Publisher Site | Google Scholar
  74. K. Rashid and P. C. Sil, “Curcumin ameliorates testicular damage in diabetic rats by suppressing cellular stress-mediated mitochondria and endoplasmic reticulum-dependent apoptotic death,” Biochimica et Biophysica Acta, vol. 1852, no. 1, pp. 70–82, 2015. View at: Publisher Site | Google Scholar
  75. K. Rashid and P. C. Sil, “Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats,” Toxicology and Applied Pharmacology, vol. 282, no. 3, pp. 297–310, 2015. View at: Publisher Site | Google Scholar
  76. W. Cai, B. Zhang, D. Duan, J. Wu, and J. Fang, “Curcumin targeting the thioredoxin system elevates oxidative stress in HeLa cells,” Toxicology and Applied Pharmacology, vol. 262, no. 3, pp. 341–348, 2012. View at: Publisher Site | Google Scholar
  77. A. K. Singh and K. Misra, “Human papilloma virus 16 E6 protein as a target for curcuminoids, curcumin conjugates and congeners for chemoprevention of oral and cervical cancers,” Interdisciplinary Sciences, vol. 5, no. 2, pp. 112–118, 2013. View at: Publisher Site | Google Scholar
  78. D. J. Klionsky, “Autophagy participates in, well, just about everything,” Cell Death and Differentiation, vol. 27, no. 3, pp. 831-832, 2020. View at: Publisher Site | Google Scholar
  79. Z. Yang and D. J. Klionsky, “Mammalian autophagy: core molecular machinery and signaling regulation,” Current Opinion in Cell Biology, vol. 22, no. 2, pp. 124–131, 2010. View at: Publisher Site | Google Scholar
  80. J. Geng and D. J. Klionsky, “Determining Atg protein stoichiometry at the phagophore assembly site by fluorescence microscopy,” Autophagy, vol. 6, no. 1, pp. 144–147, 2010. View at: Publisher Site | Google Scholar
  81. M. Cicchini, R. Chakrabarti, S. Kongara et al., “Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity,” Autophagy, vol. 10, no. 11, pp. 2036–2052, 2014. View at: Publisher Site | Google Scholar
  82. X. Qu, J. Yu, G. Bhagat et al., “Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene,” The Journal of Clinical Investigation, vol. 112, no. 12, pp. 1809–1820, 2003. View at: Publisher Site | Google Scholar
  83. Z. Yue, S. Jin, C. Yang, A. J. Levine, and N. Heintz, “Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 25, pp. 15077–15082, 2011. View at: Publisher Site | Google Scholar
  84. R.-A. Gonzalez-Polo, “The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death,” Journal of Cell Science, vol. 118, no. 14, pp. 3091–3102, 2005. View at: Publisher Site | Google Scholar
  85. J. J. Lum, R. J. DeBerardinis, and C. B. Thompson, “Autophagy in metazoans: cell survival in the land of plenty,” Nature Reviews. Molecular Cell Biology, vol. 6, no. 6, pp. 439–448, 2005. View at: Publisher Site | Google Scholar
  86. N. Chen and V. Karantza, “Autophagy as a therapeutic target in cancer,” Cancer Biology & Therapy, vol. 11, no. 2, pp. 157–168, 2014. View at: Publisher Site | Google Scholar
  87. S. Pandey and C. Chandravati, “Autophagy in cervical cancer: an emerging therapeutic target,” Asian Pacific Journal of Cancer Prevention, vol. 13, no. 10, pp. 4867–4871, 2012. View at: Publisher Site | Google Scholar
  88. R. S. DiPaola, D. Dvorzhinski, A. Thalasila et al., “Therapeutic starvation and autophagy in prostate cancer: a new paradigm for targeting metabolism in cancer therapy,” Prostate, vol. 68, no. 16, pp. 1743–1752, 2008. View at: Publisher Site | Google Scholar
  89. V. Karantza and E. White, “Role of autophagy in breast cancer,” Autophagy, vol. 3, no. 6, pp. 610–613, 2014. View at: Publisher Site | Google Scholar
  90. Q. Kang and A. Chen, “Curcumin inhibits srebp-2 expression in activated hepatic stellate cells in vitro by reducing the activity of specificity protein-1,” Endocrinology, vol. 150, no. 12, pp. 5384–5394, 2009. View at: Publisher Site | Google Scholar
  91. W. Gao, J. Y.-W. Chan, W. I. Wei, and T.-S. Wong, “Anti-cancer effects of curcumin on head and neck cancers,” Anti-Cancer Agents in Medicinal Chemistry, vol. 12, no. 9, pp. 1110–1116, 2012. View at: Publisher Site | Google Scholar
  92. T. Plengsuriyakarn, V. Viyanant, V. Eursitthichai et al., “Cytotoxicity, toxicity, and anticancer activity of Zingiber officinale Roscoe against cholangiocarcinoma,” Asian Pacific Journal of Cancer Prevention, vol. 13, no. 9, pp. 4597–4606, 2012. View at: Publisher Site | Google Scholar
  93. D. Y. Zhou, N. Ding, Z. Y. Du et al., “Curcumin analogues with high activity for inhibiting human prostate cancer cell growth and androgen receptor activation,” Molecular Medicine Reports, vol. 10, no. 3, pp. 1315–1322, 2014. View at: Publisher Site | Google Scholar
  94. J. Odot, P. Albert, A. Carlier, M. Tarpin, J. Devy, and C. Madoulet, “In vitro and in vivo anti-tumoral effect of curcumin against melanoma cells,” International Journal of Cancer, vol. 111, no. 3, pp. 381–387, 2004. View at: Publisher Site | Google Scholar
  95. S. S. Bansal, M. Goel, F. Aqil, M. V. Vadhanam, and R. C. Gupta, “Advanced drug delivery systems of curcumin for cancer chemoprevention,” Cancer Prevention Research, vol. 4, no. 8, pp. 1158–1171, 2011. View at: Publisher Site | Google Scholar
  96. H. J. Kang, S. H. Lee, J. E. Price, and L. S. Kim, “Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB in breast cancer cells and potentiates the growth inhibitory effect of paclitaxel in a breast cancer nude mice model,” The Breast Journal, vol. 15, no. 3, pp. 223–229, 2009. View at: Publisher Site | Google Scholar
  97. S.-J. Lee, H.-P. Kim, Y. Jin, A. M. K. Choi, and S. W. Ryter, “Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis,” Autophagy, vol. 7, no. 8, pp. 829–839, 2014. View at: Publisher Site | Google Scholar
  98. H. Aoki, Y. Takada, S. Kondo, R. Sawaya, B. B. Aggarwal, and Y. Kondo, “Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways,” Molecular Pharmacology, vol. 72, no. 1, pp. 29–39, 2007. View at: Publisher Site | Google Scholar
  99. Y.-L. Jia, J. Li, Z.-H. Qin, and Z.-Q. Liang, “Autophagic and apoptotic mechanisms of curcumin-induced death in K562 cells,” Journal of Asian Natural Products Research, vol. 11, no. 11, pp. 918–928, 2009. View at: Publisher Site | Google Scholar
  100. H. Qian, Y. Yang, and X. Wang, “Curcumin enhanced adriamycin-induced human liver-derived hepatoma G2 cell death through activation of mitochondria-mediated apoptosis and autophagy,” European Journal of Pharmaceutical Sciences, vol. 43, no. 3, pp. 125–131, 2011. View at: Publisher Site | Google Scholar
  101. O. Ozmen and F. Mor, “Effects of vitamin C on pathology and caspase-3 activity of kidneys with subacute endosulfan toxicity,” Biotechnic & Histochemistry, vol. 90, no. 1, pp. 25–30, 2014. View at: Publisher Site | Google Scholar
  102. D. Rastogi, R. Narayan, D. K. Saxena, and D. K. Chowdhuri, “Endosulfan induced cell death in Sertoli-germ cells of male Wistar rat follows intrinsic mode of cell death,” Chemosphere, vol. 94, pp. 104–115, 2014. View at: Publisher Site | Google Scholar
  103. B. Shao, L. Zhu, M. Dong et al., “DNA damage and oxidative stress induced by endosulfan exposure in zebrafish (Danio rerio),” Ecotoxicology, vol. 21, no. 5, pp. 1533–1540, 2012. View at: Publisher Site | Google Scholar
  104. H. Y. Sohn, C. S. Kwon, G. S. Kwon, J. B. Lee, and E. Kim, “Induction of oxidative stress by endosulfan and protective effect of lipid- soluble antioxidants against endosulfan-induced oxidative damage,” Toxicology Letters, vol. 151, no. 2, pp. 357–365, 2004. View at: Publisher Site | Google Scholar
  105. I. A. Zervos, E. Nikolaidis, S. N. Lavrentiadou et al., “Endosulfan-induced lipid peroxidation in rat brain and its effect on t-PA and PAI-1: ameliorating effect of vitamins C and E,” The Journal of Toxicological Sciences, vol. 36, no. 4, pp. 423–433, 2011. View at: Publisher Site | Google Scholar
  106. E. H. Han, H. G. Kim, E. J. Lee, and H. G. Jeong, “Endosulfan induces CYP1A1 expression mediated through aryl hydrocarbon receptor signal transduction by protein kinase C,” Toxicology Research, vol. 31, no. 4, pp. 339–345, 2015. View at: Publisher Site | Google Scholar
  107. N. S. Srikanth, P. K. Seth, and D. Desaiah, “Inhibition of calmodulin-activated Ca2(-)-ATPase by endosulfan in rat brain,” Journal of Toxicology and Environmental Health, vol. 28, no. 4, pp. 473–481, 1989. View at: Publisher Site | Google Scholar
  108. T. Ahmed, A. K. Tripathi, R. S. Ahmed et al., “Endosulfan-induced apoptosis and glutathione depletion in human peripheral blood mononuclear cells: attenuation by N-acetylcysteine,” Journal of Biochemical and Molecular Toxicology, vol. 22, no. 5, pp. 299–304, 2008. View at: Publisher Site | Google Scholar
  109. K. Kannan, R. F. Holcombe, S. K. Jain et al., “Evidence for the induction of apoptosis by endosulfan in a human T-cell leukemic line,” Molecular and Cellular Biochemistry, vol. 205, no. 1/2, pp. 53–66, 2000. View at: Publisher Site | Google Scholar
  110. O. Ozmen, “Cardiotoxicity and apoptotic activity in subacute endosulfan toxicity and the protective effect of vitamin C in rabbits: a pathological study,” Journal of Environmental Pathology, Toxicology and Oncology, vol. 32, no. 1, pp. 53–58, 2013. View at: Publisher Site | Google Scholar
  111. Y. Xu, N. Wang, Z. X. Shi, Y. B. Li, X. Q. Zhou, and Z. W. Sun, “The mechanism study of endosulfan-induced spermatogenic cell apoptosis of mouse in vitro,” Toxicology and Industrial Health, pp. 1–14, 2015. View at: Google Scholar
  112. S. Aggarwal, Y. Takada, S. Singh, J. N. Myers, and B. B. Aggarwal, “Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-?B signaling,” International Journal of Cancer, vol. 111, no. 5, pp. 679–692, 2004. View at: Publisher Site | Google Scholar
  113. A. C. Bharti, Y. Takada, S. Shishodia, and B. B. Aggarwal, “Evidence that receptor activator of nuclear factor (NF)-κB ligand can suppress cell proliferation and induce apoptosis through activation of a NF-κB-independent and TRAF6-dependent mechanism,” The Journal of Biological Chemistry, vol. 279, no. 7, pp. 6065–6076, 2004. View at: Publisher Site | Google Scholar
  114. S. Singh and B. B. Aggarwal, “Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected],” The Journal of Biological Chemistry, vol. 270, no. 42, pp. 24995–25000, 1995. View at: Publisher Site | Google Scholar
  115. S. Aggarwal, H. Ichikawa, Y. Takada, S. K. Sandur, S. Shishodia, and B. B. Aggarwal, “Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IκBα kinase and Akt activation,” Molecular Pharmacology, vol. 69, no. 1, pp. 195–206, 2006. View at: Publisher Site | Google Scholar
  116. A. C. Bharti, N. Donato, and B. B. Aggarwal, “Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells,” Journal of Immunology, vol. 171, no. 7, pp. 3863–3871, 2003. View at: Publisher Site | Google Scholar
  117. A. Mukhopadhyay, S. Banerjee, L. J. Stafford, C. Xia, M. Liu, and B. B. Aggarwal, “Curcumin-induced suppression of cell proliferation correlates with down- regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation,” Oncogene, vol. 21, no. 57, pp. 8852–8861, 2002. View at: Publisher Site | Google Scholar
  118. S. V. Bava, V. T. Puliappadamba, A. Deepti, A. Nair, D. Karunagaran, and R. J. Anto, “Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-κB and the serine/threonine kinase Akt and is independent of tubulin polymerization,” The Journal of Biological Chemistry, vol. 280, no. 8, pp. 6301–6308, 2005. View at: Publisher Site | Google Scholar
  119. C. S. Beevers, L. Chen, L. Liu, Y. Luo, N. J. G. Webster, and S. Huang, “Curcumin disrupts the mammalian target of rapamycin-raptor complex,” Cancer Research, vol. 69, no. 3, pp. 1000–1008, 2009. View at: Publisher Site | Google Scholar
  120. J. H. Woo, Y. H. Kim, Y. J. Choi et al., “Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt,” Carcinogenesis, vol. 24, no. 7, pp. 1199–1208, 2003. View at: Publisher Site | Google Scholar
  121. A. Chen, J. Xu, and A. C. Johnson, “Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1,” Oncogene, vol. 25, no. 2, pp. 278–287, 2006. View at: Publisher Site | Google Scholar
  122. K. Nakamura, Y. Yasunaga, T. Segawa et al., “Curcumin down-regulates AR gene expression and activation in prostate cancer cell lines,” International Journal of Oncology, vol. 21, no. 4, pp. 825–830, 2002. View at: Google Scholar
  123. B. K. Prusty and B. C. Das, “Constitutive activation of transcription factor AP-1 in cervical cancer and suppression of human papillomavirus (HPV) transcription and AP-1 activity in HeLa cells by curcumin,” International Journal of Cancer, vol. 113, no. 6, pp. 951–960, 2005. View at: Publisher Site | Google Scholar
  124. M. Tomita, H. Kawakami, J. N. Uchihara et al., “RETRACTED: Curcumin suppresses constitutive activation of AP-1 by downregulation of JunD protein in HTLV-1-infected T-cell lines,” Leukemia Research, vol. 30, no. 3, pp. 313–321, 2006. View at: Publisher Site | Google Scholar
  125. M. Tomita, T. Matsuda, H. Kawakami et al., “Curcumin targets Akt cell survival signaling pathway in HTLV-I-infected T-cell lines,” Cancer Science, vol. 97, no. 4, pp. 322–327, 2006. View at: Publisher Site | Google Scholar
  126. S. Z. Moghadamtousi, H. A. Kadir, P. Hassandarvish, H. Tajik, S. Abubakar, and K. Zandi, “A review on antibacterial, antiviral, and antifungal activity of curcumin,” BioMed Research International, vol. 2014, 12 pages, 2014. View at: Publisher Site | Google Scholar
  127. S.-S. Han, Y.-S. Keum, H.-J. Seo, and Y.-J. Surh, “Curcumin suppresses activation of NF-κB and AP-1 induced by phorbol ester in cultured human promyelocytic leukemia cells,” Journal of Biochemistry and Molecular Biology, vol. 35, no. 3, pp. 337–342, 2002. View at: Publisher Site | Google Scholar
  128. J. Tabeshpour, S. Banaeeyeh, F. Eisvand, T. Sathyapalan, M. Hashemzaei, and A. Sahebkar, “Effects of curcumin on ion channels and pumps: a review,” IUBMB Life, vol. 71, no. 7, pp. 812–820, 2019. View at: Publisher Site | Google Scholar
  129. V. Vauthier, C. Housset, and T. Falguieres, “Targeted pharmacotherapies for defective ABC transporters,” Biochemical Pharmacology, vol. 136, pp. 1–11, 2017. View at: Publisher Site | Google Scholar
  130. S. U. Seo, S. M. Woo, H. S. Lee, S. H. Kim, K. J. Min, and T. K. Kwon, “mTORC1/2 inhibitor and curcumin induce apoptosis through lysosomal membrane permeabilization-mediated autophagy,” Oncogene, vol. 37, no. 38, pp. 5205–5220, 2018. View at: Publisher Site | Google Scholar
  131. W. Bursch, F. Oberhammer, and R. Schulte-Hermann, “Cell death by apoptosis and its protective role against disease,” Trends in Pharmacological Sciences, vol. 13, no. 6, pp. 245–251, 1992. View at: Publisher Site | Google Scholar
  132. W.-C. Chen, Y.-A. Lai, Y.-C. Lin et al., “Curcumin suppresses doxorubicin-induced epithelial-mesenchymal transition via the inhibition of TGF-β and PI3K/AKT signaling pathways in triple-negative breast cancer cells,” Journal of Agricultural and Food Chemistry, vol. 61, no. 48, pp. 11817–11824, 2013. View at: Publisher Site | Google Scholar
  133. B. R. Seo, K. J. Min, I. J. Cho, S. C. Kim, and T. K. Kwon, “Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability,” PLoS One, vol. 9, no. 4, p. e95588, 2014. View at: Publisher Site | Google Scholar
  134. M. S. Squires, E. A. Hudson, L. Howells et al., “Relevance of mitogen activated protein kinase (MAPK) and phosphotidylinositol-3-kinase/protein kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells,” Biochemical Pharmacology, vol. 65, no. 3, pp. 361–376, 2003. View at: Publisher Site | Google Scholar
  135. X. Xu, J. Qin, and W. Liu, “Curcumin inhibits the invasion of thyroid cancer cells via down-regulation of PI3K/Akt signaling pathway,” Gene, vol. 546, no. 2, pp. 226–232, 2014. View at: Publisher Site | Google Scholar
  136. M. Laplante and D. M. Sabatini, “mTOR signaling,” Cold Spring Harbor Perspectives in Biology, vol. 4, no. 2, 2012. View at: Publisher Site | Google Scholar
  137. M. Laplante and D. M. Sabatini, “mTOR signaling in growth control and disease,” Cell, vol. 149, no. 2, pp. 274–293, 2012. View at: Publisher Site | Google Scholar
  138. J. Zhang, J. Wang, J. Xu et al., “Curcumin targets the TFEB-lysosome pathway for induction of autophagy,” Oncotarget, vol. 7, no. 46, pp. 75659–75671, 2016. View at: Publisher Site | Google Scholar
  139. C. Settembre, C. Di Malta, V. A. Polito et al., “TFEB links autophagy to lysosomal biogenesis,” Science, vol. 332, no. 6036, pp. 1429–1433, 2011. View at: Publisher Site | Google Scholar
  140. C. Settembre, R. Zoncu, D. L. Medina et al., “A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB,” The EMBO Journal, vol. 31, no. 5, pp. 1095–1108, 2012. View at: Publisher Site | Google Scholar
  141. J. X. Song, Y. R. Sun, I. Peluso et al., “A novel curcumin analog binds to and activates TFEB in vitro and in vivo independent of MTOR inhibition,” Autophagy, vol. 12, no. 8, pp. 1372–1389, 2016. View at: Publisher Site | Google Scholar
  142. L. T. Yi, S. Q. Dong, S. S. Wang et al., “Curcumin attenuates cognitive impairment by enhancing autophagy in chemotherapy,” Neurobiology of Disease, vol. 136, article 104715, 2020. View at: Publisher Site | Google Scholar
  143. P. A. Andreux, R. H. Houtkooper, and J. Auwerx, “Pharmacological approaches to restore mitochondrial function,” Nature Reviews Drug Discovery, vol. 12, no. 6, pp. 465–483, 2013. View at: Publisher Site | Google Scholar
  144. E. Deas, N. W. Wood, and H. Plun-Favreau, “Mitophagy and Parkinson's disease: The PINK1-parkin link,” Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, vol. 1813, no. 4, pp. 623–633, 2011. View at: Publisher Site | Google Scholar
  145. P. Picone, D. Nuzzo, L. Caruana, V. Scafidi, and M. Di Carlo, “Mitochondrial dysfunction: different routes to Alzheimer’s disease therapy,” Oxidative Medicine and Cellular Longevity, vol. 2014, 11 pages, 2014. View at: Publisher Site | Google Scholar
  146. G. W. Dorn and S. J. Matkovich, “Epitranscriptional regulation of cardiovascular development and disease,” The Journal of Physiology, vol. 593, no. 8, pp. 1799–1808, 2015. View at: Publisher Site | Google Scholar
  147. M. Zamora, R. Pardo, and J. A. Villena, “Pharmacological induction of mitochondrial biogenesis as a therapeutic strategy for the treatment of type 2 diabetes,” Biochemical Pharmacology, vol. 98, no. 1, pp. 16–28, 2015. View at: Publisher Site | Google Scholar
  148. R. C. Scarpulla, “Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network,” Biochimica et Biophysica Acta, vol. 1813, no. 7, pp. 1269–1278, 2011. View at: Publisher Site | Google Scholar
  149. K. Sakamoto, T. Murata, H. Chuma, M. Hori, and H. Ozaki, “Fluvastatin prevents vascular hyperplasia by inhibiting phenotype modulation and proliferation through extracellular signal-regulated kinase 1 and 2 and p38 mitogen-activated protein kinase inactivation in organ-cultured artery,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 2, pp. 327–333, 2005. View at: Publisher Site | Google Scholar
  150. C. Canto and J. Auwerx, “Caloric restriction, SIRT1 and longevity,” Trends in Endocrinology and Metabolism, vol. 20, no. 7, pp. 325–331, 2009. View at: Publisher Site | Google Scholar
  151. C. Canto and J. Auwerx, “PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure,” Current Opinion in Lipidology, vol. 20, no. 2, pp. 98–105, 2009. View at: Publisher Site | Google Scholar
  152. C. Canto, Z. Gerhart-Hines, J. N. Feige et al., “AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity,” Nature, vol. 458, no. 7241, pp. 1056–1060, 2009. View at: Publisher Site | Google Scholar
  153. Z. Gerhart-Hines, J. T. Rodgers, O. Bare et al., “Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α,” The EMBO Journal, vol. 26, no. 7, pp. 1913–1923, 2007. View at: Publisher Site | Google Scholar
  154. C. Handschin and B. M. Spiegelman, “Peroxisome proliferator-activated receptor γ coactivator 1 coactivators, energy homeostasis, and metabolism,” Endocrine Reviews, vol. 27, no. 7, pp. 728–735, 2006. View at: Publisher Site | Google Scholar
  155. J. Lin, P. Puigserver, J. Donovan, P. Tarr, and B. M. Spiegelman, “Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta ), a novel PGC-1-related transcription coactivator associated with host cell factor,” The Journal of Biological Chemistry, vol. 277, no. 3, pp. 1645–1648, 2002. View at: Publisher Site | Google Scholar
  156. P. Puigserver, J. Ribot, F. Serra et al., “Involvement of the retinoblastoma protein in brown and white adipocyte cell differentiation: Functional and physical association with the adipogenic transcription factor C/EBPα,” European Journal of Cell Biology, vol. 77, no. 2, pp. 117–123, 1998. View at: Publisher Site | Google Scholar
  157. J. Athale, A. Ulrich, N. Chou MacGarvey et al., “Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in _Staphylococcus aureus_ pneumonia in mice,” Free Radical Biology & Medicine, vol. 53, no. 8, pp. 1584–1594, 2012. View at: Publisher Site | Google Scholar
  158. N. C. MacGarvey, H. B. Suliman, R. R. Bartz et al., “Activation of mitochondrial biogenesis by heme oxygenase-1-mediated NF-E2-related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis,” American Journal of Respiratory and Critical Care Medicine, vol. 185, no. 8, pp. 851–861, 2012. View at: Publisher Site | Google Scholar
  159. C. A. Piantadosi, M. S. Carraway, A. Babiker, and H. B. Suliman, “Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1,” Circulation Research, vol. 103, no. 11, pp. 1232–1240, 2008. View at: Publisher Site | Google Scholar
  160. S. N. Schreiber, D. Knutti, K. Brogli, T. Uhlmann, and A. Kralli, “The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha),” The Journal of Biological Chemistry, vol. 278, no. 11, pp. 9013–9018, 2003. View at: Publisher Site | Google Scholar
  161. C. A. Virbasius, J. V. Virbasius, and R. C. Scarpulla, “NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators,” Genes & Development, vol. 7, no. 12a, pp. 2431–2445, 1993. View at: Publisher Site | Google Scholar
  162. J. V. Virbasius, C. A. Virbasius, and R. C. Scarpulla, “Identity of GABP with NRF-2, a multisubunit activator of cytochrome oxidase expression, reveals a cellular role for an ETS domain activator of viral promoters,” Genes & Development, vol. 7, no. 3, pp. 380–392, 1993. View at: Publisher Site | Google Scholar
  163. Q. Zhang, Y. Wu, P. Zhang et al., “Exercise induces mitochondrial biogenesis after brain ischemia in rats,” Neuroscience, vol. 205, pp. 10–17, 2012. View at: Publisher Site | Google Scholar
  164. R. Anderson and T. Prolla, “PGC-1α in aging and anti-aging interventions,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1790, no. 10, pp. 1059–1066, 2009. View at: Publisher Site | Google Scholar
  165. C. Canugovi, S. Maynard, A. C. V. Bayne et al., “The mitochondrial transcription factor A functions in mitochondrial base excision repair,” DNA Repair, vol. 9, no. 10, pp. 1080–1089, 2010. View at: Publisher Site | Google Scholar
  166. R. P. Fisher and D. A. Clayton, “Purification and characterization of human mitochondrial transcription factor 1,” Molecular and Cellular Biology, vol. 8, no. 8, pp. 3496–3509, 1988. View at: Publisher Site | Google Scholar
  167. S. D. Chen, D. I. Yang, T. K. Lin, F. Z. Shaw, C. W. Liou, and Y. C. Chuang, “Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia,” International Journal of Molecular Sciences, vol. 12, no. 10, pp. 7199–7215, 2011. View at: Publisher Site | Google Scholar
  168. M. I. Ekstrand, M. Falkenberg, A. Rantanen et al., “Mitochondrial transcription factor A regulates mtDNA copy number in mammals,” Human Molecular Genetics, vol. 13, no. 9, pp. 935–944, 2004. View at: Publisher Site | Google Scholar
  169. A. Picca and A. M. S. Lezza, “Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions: useful insights from aging and calorie restriction studies,” Mitochondrion, vol. 25, pp. 67–75, 2015. View at: Publisher Site | Google Scholar
  170. U. Hani and H. G. Shivakumar, “Solubility enhancement and delivery systems of curcumin a herbal medicine: a review,” Current Drug Delivery, vol. 11, no. 6, pp. 792–804, 2014. View at: Publisher Site | Google Scholar
  171. M. M. Yallapu, P. K. Bhusetty Nagesh, M. Jaggi, and S. C. Chauhan, “Therapeutic applications of curcumin nanoformulations,” The AAPS Journal, vol. 17, no. 6, pp. 1341–1356, 2015. View at: Publisher Site | Google Scholar
  172. M. S. Zaman, N. Chauhan, M. M. Yallapu et al., “Curcumin nanoformulation for cervical cancer treatment,” Scientific Reports, vol. 6, no. 1, 2016. View at: Publisher Site | Google Scholar
  173. J. Lone, J. H. Choi, S. W. Kim, and J. W. Yun, “Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes,” The Journal of Nutritional Biochemistry, vol. 27, pp. 193–202, 2016. View at: Publisher Site | Google Scholar
  174. Q. Ma, “Role of Nrf 2 in oxidative stress and toxicity,” Annual Review of Pharmacology and Toxicology, vol. 53, no. 1, pp. 401–426, 2013. View at: Publisher Site | Google Scholar
  175. M. Negrette-Guzman, W. R. Garcia-Nino, E. Tapia et al., “Curcumin attenuates gentamicin-induced kidney mitochondrial alterations: possible role of a mitochondrial biogenesis mechanism,” Evidence-based Complementary and Alternative Medicine, vol. 2015, 16 pages, 2015. View at: Publisher Site | Google Scholar
  176. R. D. Ray Hamidie, T. Yamada, R. Ishizawa, Y. Saito, and K. Masuda, “Curcumin treatment enhances the effect of exercise on mitochondrial biogenesis in skeletal muscle by increasing cAMP levels,” Metabolism, vol. 64, no. 10, pp. 1334–1347, 2015. View at: Publisher Site | Google Scholar
  177. L. Liu, W. Zhang, L. Wang et al., “Curcumin prevents cerebral ischemia reperfusion injury via increase of mitochondrial biogenesis,” Neurochemical Research, vol. 39, no. 7, pp. 1322–1331, 2014. View at: Publisher Site | Google Scholar
  178. Z. Song, X. Revelo, W. Shao et al., “Dietary curcumin intervention targets mouse white adipose tissue inflammation and brown adipose tissue UCP1 expression,” Obesity (Silver Spring), vol. 26, no. 3, pp. 547–558, 2018. View at: Publisher Site | Google Scholar
  179. K. Palikaras, E. Lionaki, and N. Tavernarakis, “Mitophagy: in sickness and in health,” Molecular & Cellular Oncology, vol. 3, no. 1, p. e1056332, 2015. View at: Publisher Site | Google Scholar
  180. K. Palikaras and N. Tavernarakis, “Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis,” Experimental Gerontology, vol. 56, pp. 182–188, 2014. View at: Publisher Site | Google Scholar
  181. T. M. Durcan and E. A. Fon, “The three “P”s of mitophagy: PARKIN, PINK1, and post-translational modifications,” Genes & Development, vol. 29, no. 10, pp. 989–999, 2015. View at: Publisher Site | Google Scholar
  182. T. M. Durcan and E. A. Fon, “USP8 and PARK2/parkin-mediated mitophagy,” Autophagy, vol. 11, no. 2, pp. 428-429, 2015. View at: Publisher Site | Google Scholar
  183. M. Song, G. Gong, Y. Burelle et al., “Interdependence of Parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts,” Circulation Research, vol. 117, no. 4, pp. 346–351, 2015. View at: Publisher Site | Google Scholar
  184. L.-S. Chin and L. Li, “Ubiquitin phosphorylation in Parkinson’s disease: implications for pathogenesis and treatment,” Translational Neurodegeneration, vol. 5, no. 1, 2016. View at: Publisher Site | Google Scholar
  185. M. H. Irwin, W. H. Moos, D. V. Faller, K. Steliou, and C. A. Pinkert, “Epigenetic treatment of neurodegenerative disorders: Alzheimer and Parkinson diseases,” Drug Development Research, vol. 77, no. 3, pp. 109–123, 2016. View at: Publisher Site | Google Scholar
  186. S. Rajagopalan, A. Rane, S. J. Chinta, and J. K. Andersen, “Regulation of ATP13A2 via PHD2-HIF1α signaling is critical for cellular iron homeostasis: implications for Parkinson’s disease,” The Journal of Neuroscience, vol. 36, no. 4, pp. 1086–1095, 2016. View at: Publisher Site | Google Scholar
  187. M. Tong and J. Sadoshima, “Mitochondrial autophagy in cardiomyopathy,” Current Opinion in Genetics & Development, vol. 38, pp. 8–15, 2016. View at: Publisher Site | Google Scholar
  188. C. Wang, X. Zhang, Z. Teng, T. Zhang, and Y. Li, “Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice,” European Journal of Pharmacology, vol. 740, pp. 312–320, 2014. View at: Publisher Site | Google Scholar
  189. X. Wang, A. W. Leung, J. Luo, and C. Xu, “TEM observation of ultrasound-induced mitophagy in nasopharyngeal carcinoma cells in the presence of curcumin,” Experimental and Therapeutic Medicine, vol. 3, no. 1, pp. 146–148, 2012. View at: Publisher Site | Google Scholar
  190. J. Chen, T. Xu, and C. Chen, “The critical roles of miR-21 in anti-cancer effects of curcumin,” Annals of Translational Medicine, vol. 3, no. 21, p. 330, 2015. View at: Publisher Site | Google Scholar
  191. J. Zhang, Y. Du, C. Wu et al., “Curcumin promotes apoptosis in human lung adenocarcinoma cells through miR-186 signaling pathway,” Oncology Reports, vol. 24, no. 5, pp. 1217–1223, 2010. View at: Publisher Site | Google Scholar
  192. A. A. Momtazi, F. Shahabipour, S. Khatibi, T. P. Johnston, M. Pirro, and A. Sahebkar, “Curcumin as a microRNA regulator in cancer: a review,” Reviews of Physiology, Biochemistry and Pharmacology, vol. 171, pp. 1–38, 2016. View at: Publisher Site | Google Scholar
  193. H. Mirzaei, A. Masoudifar, A. Sahebkar et al., “MicroRNA: a novel target of curcumin in cancer therapy,” Journal of Cellular Physiology, vol. 233, no. 4, pp. 3004–3015, 2018. View at: Publisher Site | Google Scholar
  194. J. Baell and M. A. Walters, “Chemistry: chemical con artists foil drug discovery,” Nature, vol. 513, no. 7519, pp. 481–483, 2014. View at: Publisher Site | Google Scholar
  195. J. B. Baell and G. A. Holloway, “New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays,” Journal of Medicinal Chemistry, vol. 53, no. 7, pp. 2719–2740, 2010. View at: Publisher Site | Google Scholar
  196. Y. Hu and J. Bajorath, “Compound promiscuity: what can we learn from current data?” Drug Discovery Today, vol. 18, no. 13-14, pp. 644–650, 2013. View at: Publisher Site | Google Scholar
  197. K. M. Nelson, J. L. Dahlin, J. Bisson, J. Graham, G. F. Pauli, and M. A. Walters, “The essential medicinal chemistry of curcumin,” Journal of Medicinal Chemistry, vol. 60, no. 5, pp. 1620–1637, 2017. View at: Publisher Site | Google Scholar
  198. K. M. Nelson, J. L. Dahlin, J. Bisson, J. Graham, G. F. Pauli, and M. A. Walters, “Curcumin may (not) defy science,” ACS Medicinal Chemistry Letters, vol. 8, no. 5, pp. 467–470, 2017. View at: Publisher Site | Google Scholar
  199. G. Padmanaban and V. A. Nagaraj, “Curcumin may defy medicinal chemists,” ACS Medicinal Chemistry Letters, vol. 8, no. 3, p. 274, 2017. View at: Publisher Site | Google Scholar
  200. A. B. Kunnumakkara, D. Bordoloi, G. Padmavathi et al., “Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases,” British Journal of Pharmacology, vol. 174, no. 11, pp. 1325–1348, 2017. View at: Publisher Site | Google Scholar
  201. S. Richard, A. Saric, M. Boucher et al., “Antioxidative theranostic iron oxide nanoparticles toward brain tumors imaging and ROS production,” ACS Chemical Biology, vol. 11, no. 10, pp. 2812–2819, 2016. View at: Publisher Site | Google Scholar
  202. M. Suzuki, L. Bachelet-Violette, F. Rouzet et al., “Ultrasmall superparamagnetic iron oxide nanoparticles coated with fucoidan for molecular MRI of intraluminal thrombus,” Nanomedicine (London, England), vol. 10, no. 1, pp. 73–87, 2015. View at: Publisher Site | Google Scholar
  203. S. S. Hann, J. Chen, Z. Wang, J. Wu, F. Zheng, and S. Zhao, “Targeting EP4 by curcumin through cross talks of AMP-dependent kinase alpha and p38 mitogen-activated protein kinase signaling: the role of PGC-1α and Sp1,” Cellular Signalling, vol. 25, no. 12, pp. 2566–2574, 2013. View at: Publisher Site | Google Scholar
  204. M. M. Rechtman, O. Har-Noy, I. Bar-Yishay et al., “Curcumin inhibits hepatitis B virus via down-regulation of the metabolic coactivator PGC-1α,” FEBS Letters, vol. 584, no. 11, pp. 2485–2490, 2010. View at: Publisher Site | Google Scholar
  205. P. Du, H. Cao, H. R. Wu et al., “Blocking Bcl-2 leads to autophagy activation and cell death of the HEPG2 liver cancer cell line,” Asian Pacific Journal of Cancer Prevention, vol. 14, no. 10, pp. 5849–5854, 2013. View at: Publisher Site | Google Scholar
  206. A. Hematulin, K. Ingkaninan, N. Limpeanchob, and D. Sagan, “Ethanolic extract from Derris scandens Benth mediates radiosensitzation via two distinct modes of cell death in human colon cancer HT-29 cells,” Asian Pacific Journal of Cancer Prevention, vol. 15, no. 4, pp. 1871–1877, 2014. View at: Publisher Site | Google Scholar
  207. Y. Wan, Y. Liang, F. Liang et al., “A curcumin analog reduces levels of the Alzheimer’s disease-associated Amyloid-β protein by modulating AβPP processing and autophagy,” Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 761–771, 2019. View at: Publisher Site | Google Scholar
  208. S. Vijayarathna, S. Gothai, S. L. Jothy, Y. Chen, J. R. Kanwar, and S. Sasidharan, “Can cancer therapy be achieved by bridging apoptosis and autophagy: a method based on microRNA-dependent gene therapy and phytochemical targets,” Asian Pacific Journal of Cancer Prevention, vol. 16, no. 17, pp. 7435–7439, 2015. View at: Publisher Site | Google Scholar
  209. S. Vijayarathna, C. Oon, S. Jothy, Y. Chen, J. Kanwar, and S. Sasidharan, “MicroRNA pathways: an emerging role in identification of therapeutic strategies,” Current Gene Therapy, vol. 14, no. 2, pp. 112–120, 2014. View at: Publisher Site | Google Scholar
  210. A. Pavan, G. Silva, D. Jornada et al., “Unraveling the anticancer effect of curcumin and resveratrol,” Nutrients, vol. 8, no. 11, p. 628, 2016. View at: Publisher Site | Google Scholar
  211. Y.-J. Chang, C. Y. Huang, C. S. Hung, W. Y. Chen, and P. L. Wei, “GRP78 mediates the therapeutic efficacy of curcumin on colon cancer,” Tumour Biology, vol. 36, no. 2, pp. 633–641, 2015. View at: Publisher Site | Google Scholar
  212. L. X. Chen, Y. J. He, S. Z. Zhao et al., “Inhibition of tumor growth and vasculogenic mimicry by curcumin through down-regulation of the EphA2/PI3K/MMP pathway in a murine choroidal melanoma model,” Cancer Biology & Therapy, vol. 11, no. 2, pp. 229–235, 2014. View at: Publisher Site | Google Scholar
  213. C. Q. Chen, K. Yu, Q. X. Yan et al., “Pure curcumin increases the expression of SOCS1 and SOCS3 in myeloproliferative neoplasms through suppressing class Ι histone deacetylases,” Carcinogenesis, vol. 34, no. 7, pp. 1442–1449, 2013. View at: Publisher Site | Google Scholar
  214. B. Chen, Y. Zhang, Y. Wang, J. Rao, X. Jiang, and Z. Xu, “Curcumin inhibits proliferation of breast cancer cells through Nrf2-mediated down-regulation of Fen1 expression,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 143, pp. 11–18, 2014. View at: Publisher Site | Google Scholar
  215. S. M. Gao, J. J. Yang, C. Q. Chen et al., “Pure curcumin decreases the expression of WT1 by upregulation of miR-15a and miR-16-1 in leukemic cells,” Journal of Experimental & Clinical Cancer Research, vol. 31, no. 1, p. 27, 2012. View at: Publisher Site | Google Scholar
  216. Y. Guo, L. Shu, C. Zhang, Z. Y. Su, and A. N. T. Kong, “Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene _DLEC1_,” Biochemical Pharmacology, vol. 94, no. 2, pp. 69–78, 2015. View at: Publisher Site | Google Scholar
  217. L. Wang, X. Ye, X. Cai et al., “Curcumin suppresses cell growth and invasion and induces apoptosis by down-regulation of Skp2 pathway in glioma cells,” Oncotarget, vol. 6, no. 20, pp. 18027–18037, 2015. View at: Publisher Site | Google Scholar
  218. Z. Zhao, C. Li, H. Xi, Y. Gao, and D. Xu, “Curcumin induces apoptosis in pancreatic cancer cells through the induction of forkhead box O1 and inhibition of the PI3K/Akt pathway,” Molecular Medicine Reports, vol. 12, no. 4, pp. 5415–5422, 2015. View at: Publisher Site | Google Scholar
  219. M. Jiang, O. Huang, X. Zhang et al., “Curcumin induces cell death and restores tamoxifen sensitivity in the antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9,” Molecules, vol. 18, no. 1, pp. 701–720, 2013. View at: Publisher Site | Google Scholar
  220. M. Sun, Z. Estrov, Y. Ji, K. R. Coombes, D. H. Harris, and R. Kurzrock, “Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells,” Molecular Cancer Therapeutics, vol. 7, no. 3, pp. 464–473, 2008. View at: Publisher Site | Google Scholar
  221. S. Ali, A. Ahmad, S. Banerjee et al., “Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF,” Cancer Research, vol. 70, no. 9, pp. 3606–3617, 2010. View at: Publisher Site | Google Scholar
  222. G. Mudduluru, J. N. George-William, S. Muppala et al., “Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer,” Bioscience Reports, vol. 31, no. 3, pp. 185–197, 2011. View at: Publisher Site | Google Scholar
  223. J. Yang, Y. Cao, J. Sun, and Y. Zhang, “Curcumin reduces the expression of Bcl-2 by upregulating miR-15a and miR-16 in MCF-7 cells,” Medical Oncology, vol. 27, no. 4, pp. 1114–1118, 2010. View at: Publisher Site | Google Scholar
  224. N. Wang, T. Feng, X. Liu, and Q. Liu, “Curcumin inhibits migration and invasion of non-small cell lung cancer cells through up-regulation of miR-206 and suppression of PI3K/AKT/mTOR signaling pathway,” Acta Pharmaceutica, vol. 70, no. 3, pp. 399–409, 2020. View at: Publisher Site | Google Scholar
  225. Y. Li, Y. Gu, N. Tang, Y. Liu, and Z. Zhao, “miR-22-Notch signaling pathway is involved in the regulation of the apoptosis and autophagy in human ovarian cancer cells,” Biological & Pharmaceutical Bulletin, vol. 41, no. 8, pp. 1237–1242, 2018. View at: Publisher Site | Google Scholar
  226. Z. Han, J. Zhang, K. Zhang, and Y. Zhao, “Curcumin inhibits cell viability, migration, and invasion of thymic carcinoma cells via downregulation of microRNA-27a,” Phytotherapy Research, 2020. View at: Publisher Site | Google Scholar
  227. L. Zhou, Y. Lu, J. S. Liu et al., “The role of miR-21/RECK in the inhibition of osteosarcoma by curcumin,” Molecular and Cellular Probes, vol. 51, p. 101534, 2020. View at: Publisher Site | Google Scholar
  228. S. Sreenivasan, K. Thirumalai, R. Danda, and S. Krishnakumar, “Effect of curcumin on miRNA expression in human Y79 retinoblastoma cells,” Current Eye Research, vol. 37, no. 5, pp. 421–428, 2012. View at: Publisher Site | Google Scholar

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