Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2018 / Article
Special Issue

Natural Bioactive Compounds Acting Against Oxidative Stress in Chronic, Degenerative, and Infectious Diseases

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Review Article | Open Access

Volume 2018 |Article ID 1826170 | https://doi.org/10.1155/2018/1826170

Islam Rady, Melissa B. Bloch, Roxane-Cherille N. Chamcheu, Sergette Banang Mbeumi, Md Rafi Anwar, Hadir Mohamed, Abiola S. Babatunde, Jules-Roger Kuiate, Felicite K. Noubissi, Khalid A. El Sayed, G. Kerr Whitfield, Jean Christopher Chamcheu, "Anticancer Properties of Graviola (Annona muricata): A Comprehensive Mechanistic Review", Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 1826170, 39 pages, 2018. https://doi.org/10.1155/2018/1826170

Anticancer Properties of Graviola (Annona muricata): A Comprehensive Mechanistic Review

Academic Editor: Italo Tempera
Received15 Feb 2018
Accepted03 Jun 2018
Published30 Jul 2018

Abstract

Graviola (Annona muricata) is a small deciduous tropical evergreen fruit tree, belonging to the Annonaceae family, and is widely grown and distributed in tropical and subtropical regions around the world. The aerial parts of graviola have several functions: the fruits have been widely used as food confectionaries, while several preparations, especially decoctions of the bark, fruits, leaves, pericarp, seeds, and roots, have been extensively used in traditional medicine to treat multiple ailments including cancers by local communities in tropical Africa and South America. The reported therapeutic benefits of graviola against various human tumors and disease agents in in vitro culture and preclinical animal model systems are typically tested for their ability to specifically target the disease, while exerting little or no effect on normal cell viability. Over 212 phytochemical ingredients have been reported in graviola extracts prepared from different plant parts. The specific bioactive constituents responsible for the major anticancer, antioxidant, anti-inflammatory, antimicrobial, and other health benefits of graviola include different classes of annonaceous acetogenins (metabolites and products of the polyketide pathway), alkaloids, flavonoids, sterols, and others. This review summarizes the current understanding of the anticancer effects of A. muricata and its constituents on diverse cancer types and disease states, as well as efficacy and safety concerns. It also includes discussion of our current understanding of possible mechanisms of action, with the hope of further stimulating the development of improved and affordable therapies for a variety of ailments.

1. Introduction

Cancer is the second leading cause of mortality worldwide. Over 10 million new patients are diagnosed with cancer annually with over 6 million associated deaths, representing roughly 12% of worldwide mortality [1]. The occurrence of new cancer cases is expected to grow by about 70% over the next two decades and estimated to reach over 15 million new cases diagnosed annually by the year 2020 [2]. This rapid increase is due to both an aging and growing population, along with carcinogens, infections, genetic mutations, hormones, immune conditions, and the adoption of behavioral and dietary risk factors, such as smoking, unhealthy diet, physical inactivity, and environmental pollutants [3]. The risk factors may act singly or in concert to cause mutation of normal cells [4]. Many of these mutations alter the expression or activity of key gene products, causing unregulated cell division leading to cancer. Currently, the main cancer treatment modalities are surgery, radiation-based therapy, chemotherapy, gene therapy, and/or hormonal therapy, either singly or in combination [1]. The most commonly used chemotherapy drugs are antimetabolites, DNA-interacting agents, antitubulin agents, hormones, and molecular targeting agents, all of which work to destroy cancerous cells or limit their proliferation [5]. However, most cytotoxic drugs act on both cancerous and healthy cells and therefore elicit side effects such as hair loss, bone marrow suppression, drug resistance, gastrointestinal lesions, neurologic dysfunction, and cardiac toxicity [5]. Consequently, development of new anticancer agents with higher efficacy, selectivity, and little or no side effects is an urgent goal.

Natural products, especially phytochemicals, have been used to help mankind sustain health since the dawn of medicine [4]. Phytotherapy (also called herbalism or herbal medicine) has provided remedies for ailments, including cancer, to the present day [6]. Dietary phytochemicals have many built-in advantages over synthetic compounds due to their proven safety, low cost, and oral bioavailability [7]. However, it is only recently that researchers have begun to elucidate the mode of action of plant-derived agents at the molecular, cellular, and tissue level [810]. Many natural products have now been extensively researched, and numerous compounds have exhibited anticancer and other beneficial actions in modern controlled studies. Most anticancerous natural products interfere with the initiation, development, and progression of cancer by modulating various mechanisms including cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis [11].

Extracts from Annona muricata (also known as graviola) are among a myriad of botanical products which have shown promising medicinal value [1214]. Studies have linked A. muricata-derived compounds (Table 1 and Figure 1) to a variety of anticancer effects including cytotoxicity [1518], induction of apoptosis [1927], necrosis [28], and inhibition of proliferation [25, 2931] on a variety of cancer cell lines, including breast [32], prostate [29], colorectal [25], lung [16], leukemia [33], renal [34], pancreatic [15], hepatic [24], oral [35], melanoma [36], cervical [37], and ovarian cancers [38]. Moreover, all aerial parts of this plant, including the bark, fruit, leaves, root, and seeds, are used as natural medicines in the tropics [39]. However, there is a need for more rigorous studies to establish safe and effective care regimes. This review summarizes the recent advances in the application and mechanisms of A. muricata extracts against several cancers both in vitro and in vivo.


Extract (solvent)Cancers (cell lines)

n-HexaneCervical (HeLa) cancer [37]
ChloroformCervical (HeLa) cancer [37]
PentaneMelanoma (A375) cancer [36]
n-Butanolic(MDA-MB-435S) cancer [89], now known as a melanoma cell line [90]
DMSOPancreatic (Capan-1 [92], FG/COLO357, and CD18/HPAF [28]) cancer
Fungal strainBreast (MCF-7) [38], colorectal (HTC-8) [38], lung cancer (A549) [38], hepatic (Bel-7402) [38], gastric (BGC-823) [38], and ovarian (A2780) [38] cancers
H2OSquamous cell carcinoma (SCC-25) [91], melanoma (A375) [36], prostate (PC-3) [21], pancreatic (CD18/HPAF) [28], and breast cancer patients [118]
HexaneBreast (MCF-7 and MDA-MB-231) [31], colorectal (HT-29 and HCT-116) [26], lung cancer (A549) [31], leukemic (U-937) [33, 46], pancreatic (Capan-1) [92], and hepatic (Hep G2) [31] cancers
Ethyl acetateBreast (MCF-7 and MDA-MB-231) [31], colorectal (HT-29 and HCT-116) [25], lung (A549) [31], leukemic (U-937) [33, 46, 131], hepatic (Hep G2) [31], and cervical (HeLa) [37] cancers.
EthanolEhrlich ascite carcinoma (EACC) [93], breast (MCF-7 [45], MDA-MB-231-BCRP clone 23 [77, 139], T47D [22], MDA and SKBR3 [93]), colorectal [20] [140] (COLO-205 and DLD-1) [94], lung (H-460) [45, 95], leukemic (K562 [19] [96], ECV304 [96] and HL-60 [27]), stomach (C-678) [95], melanoma (A375) [36], skin [141], glioma (SF-268) [45], and cervical (HeLa) [37] cancers
MethanolBreast (MCF-7 and MDA-MB-231 [31], MDA-MB-231-pcDNA3, and MDA-MB-231-BCRP clone 23 [24]), colorectal (HT-29 and HCT-116 [26], HCT116 (p53+/+), and HCT116 (p53/) [24]), lung (A549 [31] and NCI-H292 [113]), leukemic (U-937 [33, 46], CCRF-CEM, and CEM/ADR5000 [24]), hepatic (Hep G2 [24, 31] and Hep 2,2,15 [31]), glioma (U87MG and U87MG.ΔEGFR) [24], and laryngeal (currently cervical HeLa; Hep-2) [113] cancers

2. Botanical Description and Distribution

Annona muricata is a lowland tropical, fruit-bearing tree of the family Annonaceae found in the rainforests of Africa, South America, and Southeast Asia. A. muricata, commonly known as soursop, graviola, guanabana, or Brazilian paw-paw, has large, glossy, dark green leaves [4, 40], with edible, green heart-shaped fruits [4, 41]. Soft, curved spines cover the leathery skin of the fruits, each of which may contain 55–170 black seeds distributed in a creamy white flesh with a characteristic aroma and flavor [41, 42]. All portions (leaves [16, 18, 31, 38, 43, 44], pericarp [24, 45, 46], fruits [4, 30, 47], seeds [4750], and roots [27]) of A. muricata have been used in traditional medicine, but the most widely used in the preparations of traditional medical decoctions are stem barks, roots, seeds, and leaves [51, 52]. Coria-Téllez et al. have reported 212 bioactive compounds in A. muricata extracts [41]. Reports in the literature indicate that seventy-four of these bioactive compounds exhibit a variety of anticancer effects in preclinical cell culture and animal model systems. Several dozen annonaceous acetogenins have been studied (59 of which are listed alphabetically in Table 2, with key structural features summarized in Figure 2). Moreover, at least ten solvent extracts (Table 1) in addition to an extract from fungi (Periconia sp.) collected on A. muricata that contains bioactive compounds (Figure 1) have been tested for their anticancer properties and other health benefits.


Compound namesStructureMolecular formulaMWT (g/mol)Cancer cell lines tested on

Annocatacin AC35H62O6578.88Hepatic (Hep G2 and Hep 2,2,15) cancer [80]
Annocatacin BC35H62O6578.88Hepatic (Hep G2 and Hep 2,2,15) cancer [80]
AnnocatalinC35H64O7596.89Hepatic (Hep G2 and Hep 2,2,15) cancer [81]
AnnohexocinC35H64O9628.888Breast (MCF-7), prostate (PC-3), colorectal (HT-29), lung (A549), renal (A498) and pancreatic (PACA-2) cancers [34]
Annomuricin AC35H64O8612.889Breast (MCF-7), colorectal (HT-29), lung (A549) [17], and leukemic (U-937) [46] cancers
Annomuricin BC35H64O8612.889Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [17]
Annomuricin CC35H64O8612.889Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [86]
Annomuricin EC35H64O8612.889Breast (MCF-7), prostate (PC-3), lung (A549), renal (A498), pancreatic (PACA) [16], and colorectal (HT-29) cancers [16, 25]
AnnomutacinC37H68O7624.944Breast cancer (MCF-7), colorectal (HT-29), and lung cancers (A549) [43]
AnnonacinC35H64O7596.89
Annonacin AC35H64O7596.89Leukemia (U-937) [46]
AnnonacinoneC35H62O7594.874Oral cancer (KB) [35]
Annopentocin AC35H64O8612.889Breast (MCF-7), prostate (PC-3), colorectal (HT-29), lung (A549), renal (A498), and pancreatic (PACA-2) cancers [32]
Annopentocin BC35H64O8612.889Breast (MCF-7), prostate (PC-3), colorectal (HT-29), lung (A549), renal (A498), and pancreatic (PACA-2) cancers [32]
Annopentocin CC35H64O8612.889Breast (MCF-7), prostate (PC-3), colorectal (HT-29), lung (A549), renal (A498), and pancreatic (PACA-2) cancers [32]
ArianacinC35H64O7596.89Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [85]
CorossolinC35H64O6580.891Hepatic (Hep G2 and Hep 2,2,15) [82] and oral (KB) cancers [35]
CorossoloneC35H62O6578.875Hepatic cancer (Hep G2 and Hep 2,2,15) [82] and oral (KB) cancers [35, 83]
GigantetrocinC35H64O7596.89Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [49]
Gigantetrocin AC35H64O7596.89Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [50]
Gigantetrocin BC35H64O7596.89Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [17, 50]
GoniothalamicinC35H64O7596.89Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [49]
IsoannonacinC35H64O7596.89Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [48]
Isoannonacin-10-oneC35H62O7594.874Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [49]
JavoricinC35H64O7596.89Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [85]
LongifolicinC35H64O6580.891Hepatic (Hep G2 and Hep 2,2,15) cancer [82]
MuricapentocinC35H64O8612.889Breast (MCF-7), prostate (PC-3), colorectal (HT-29), lung cancer (A549), renal (A498), and pancreatic (PACA) cancers [16]
MuricatacinC17H32O3284.44Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [48]
Muricatetrocin AC35H64O7596.89Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [17, 50]
Muricatetrocin BC35H64O7596.89Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [17, 50]
Muricatocin AC35H64O8612.889Breast (MCF-7), colorectal (HT-29) and lung (A549) cancers [44]
Muricatocin BC35H64O8612.889Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [44]
Muricatocin CC35H64O8612.889Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [86]
MuriceninProstate (PC-3) cancer [30]
Muricin AC35H64O7596.878Hepatic (Hep G2 and Hep 2,2,15) cancer [82]
Muricin BC35H64O7596.878Hepatic (Hep G2 and Hep 2,2,15) cancer [82]
Muricin CC35H64O7596.878Hepatic (Hep G2 and Hep 2,2,15) cancer [82]
Muricin DC33H60O7568.836Hepatic (Hep G2 and Hep 2,2,15) cancer [82]
Muricin EHepatic (Hep G2 and Hep 2,2,15) cancer [82]
Muricin FC35H62O7594.874Hepatic (Hep G2 and Hep 2,2,15) cancer [82]
Muricin GHepatic (Hep G2 and Hep 2,2,15) cancer [82]
Muricin HC35H64O6580.891Hepatic (Hep G2 and Hep 2,2,15) cancer [81]
Muricin IC37H66O6606.929Hepatic (Hep G2 and Hep 2,2,15) cancer [81]
Muricin JC22H38O7414.2618Prostate (PC-3) cancer [29]
Muricin KC24H42O7442.2931Prostate (PC-3) cancer [29]
Muricin LC24H42O7442.2931Prostate (PC-3) cancer [29]
Muricin MC24H42O7442.2931Prostate (PC-3) cancer [30]
Muricin NC22H38O7414.2618Prostate (PC-3) cancer [30]
MuricoreacinC35H64O9628.4550Breast (MCF-7), prostate (PC-3), colorectal (HT-29), lung cancer (A549), renal cancer (A498), and pancreatic (PACA-2) cancers [47]
Murihexocin AC35H64O9628.888Breast (MCF-7), prostate (PC-3), colorectal (HT-29), lung (A549), renal (A498), and pancreatic (PACA-2) cancers [15]
Murihexocin BC35H64O9628.4550Breast (MCF-7), prostate (PC-3), colorectal (HT-29), lung (A549), renal (A498), and pancreatic (PACA-2) cancers [15]
Murihexocin CC31H56O9572.3924Breast (MCF-7), prostate (PC-3), colorectal (HT-29), lung cancer (A549), renal cancer (A498), and pancreatic (PACA-2) cancers [47]
MurisolinC35H63NO6593.4655Oral (KB) cancer [35]
SolaminC35H64O5564.892Oral (KB) cancer [35]
VinblastineC46H58N4O9810.989Oral (KB) cancer [35]
cis-AnnomontacinC37H68O7624.4965Hepatic (Hep G2 and Hep 2,2,15) cancer [88]
cis-AnnonacinC35H64O7596.88Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [85]
cis-Annonacin-10-oneC35H62O7594.874Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [85]
cis-CorossoloneC35H62O6578.875Hepatic (Hep G2 and Hep 2,2,15) cancer [81]
cis-GoniothalamicinC35H64O7596.89Breast (MCF-7), colorectal (HT-29), and lung (A549) cancers [85]

A. muricata-derived preparations have been utilized to treat numerous ailments, making this plant an ethnomedically important species. In developing tropical countries including Africa, different parts of A. muricata are being used to treat conditions such as diabetes [53, 54], coughs, skin diseases [55], and cancers [2527, 5658]. Furthermore, in both Jamaica [59] and Trinidad [60], A. muricata is the most prevalently used herbal remedy in the treatment of most cancers. For example, in Jamaica, a large proportion of cancer patients use medicinal plants in self-medicating practices, with A. muricata being commonly used (along with Petiveria alliacea) for treating breast and prostate cancers, respectively [59].

A. muricata has also been used, mainly in developing tropical countries, for the treatment of arthritis [61], hypertension [62], snake bite [63], diarrhea [59], headache [64], and malaria [65]. In addition, it has been mentioned as an antimicrobial [66], antidiabetic [54], anti-inflammatory [67], antiprotozoan [68], antioxidant, insecticide [69], larvicide [70], and anticancer [71]. Although these uses of A. muricata strongly imply the presence of bioactive compounds with medical benefits, a full insight into the potential of A. muricata in the treatment of disease will require the identification of specific bioactive compounds and a scientifically rigorous demonstration of their ability to improve health outcomes.

3. Anticancer Effects

More than 47% of current anticancer drugs on the market are natural products, their derivatives or natural product synthetic mimics, and more than 25,000 identified phytochemicals have been shown to possess potent anticancer activities [72, 73]. The aerial parts of graviola have been extensively studied with several reported in vitro and in vivo pharmacological activities, and have been shown to be effective in the management of several cancer types. The detailed molecular mechanisms of action of various graviola organs against various cancers are summarized in tabular format (Table 3 and Figure 3).


CancersCell linesChemical compound or solventClassPlant partDose, IC50, ED50, GI50, LC50, IC25, and/or MICAnticancer effects

Breast cancerMCF-7Annomuricin AAGELeafCytotoxic activity [17]
Annomuricin B
Annomuricin CAGELeaf—–—Cytotoxic activity [86]
Annomuricin EAGELeafCytotoxic activity [16]
Muricatocin CAGELeaf—–—Cytotoxic activity [86]
MuricapentocinAGELeafCytotoxic activity [16]
AnnomutacinAGELeafCytotoxic activity [43]
(2,4-cis)-10R-Annonacin-A-one + (2,4-trans)-10R-annonacin-A-oneAGELeaf
AnnohexocinAGELeafSignificant cytotoxic activity [34]
Muricatocin AAGELeafCytotoxic activity [44]
Muricatocin BAGELeaf
Annopentocin AAGELeafCytotoxic activity [32]
Annopentocin BAGELeaf
Annopentocin CAGELeaf
cis-Annomuricin-D-one + trans-annomuricin-D-oneAGEsLeaf
Murihexocin AAGELeafSignificant cytotoxic activity [15]
Murihexocin BAGELeaf
Murihexocin CAGESeedCytotoxic activity [47]
MuricoreacinAGESeed
MuricatacinAGESeedCytotoxic activity [48]
IsoannonacinAGESeedCytotoxic activity [49]
Isoannonacin-10-oneAGESeed
GoniothalamicinAGESeed
GigantetrocinAGESeed and/or leaf
Gigantetrocin AAGESeedCytotoxic activity [50]
Muricatetrocin AAGESeed and/or leafCytotoxic activity [17, 50]
Muricatetrocin BAGESeed
Gigantetrocin BAGESeed
cis-AnnonacinAGESeedCytotoxic activity [85]
cis-Annonacin-10-oneAGESeed
cis-GoniothalamicinAGESeed
ArianacinAGELeaf
JavoricinAGELeaf
HexaneExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL; Significantly reduced cell proliferation in cancer cells [31]
Ethyl acetateExtractFruitDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL;
MethanolExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL;
———ExtractLeaf0, 50, 100, 150, and 200 μg/mL; Inhibited growth of cancer cells [23]
Ethanol (95%)ExtractLeafCytotoxic activity [45]
(+)-(3S,6S,7R,8S)-Periconone AFungal strain ExtractLeaf0.01–10 μmol/mLCytotoxic activity [38]
(−)-(1R,4R,6S,7S)-2-Caren-4,8-olide
MDA-MB-231HexaneExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL; Significantly reduced cell proliferation in cancer cells [31]
Ethyl acetateExtractFruitDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL; Significantly reduced cell proliferation in cancer cells [31]
MethanolExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL;
———ExtractSeedDoses: 50, 100, 150, and 200 μg/mL; Inhibited the growth of cancer cells [23]
MDA-MB-231-pcDNA3MethanolExtractPericarpCytotoxic activity [24]
MethanolExtractLeaf
MethanolExtractseed
MDA-MB-231-BCRP clone 23MethanolExtractPericarp
MethanolExtractSeed
MethanolExtractLeaf
———Ethanolic component (7,12-dimethylbenzeneanthracene (DMBA))ExtractFruitThree groups of albino mice treated intragastrically by gavage for 6 weeks: 20 mg/mL/week of DMBA + 200 mg/mL/day of extract, 20 mg/mL/week of DMBA + 100 mg/mL/day of extract and 20 mg/mL/week of DMBA + 50 mg/mL/day of extract [139]Prevented DMBA-induced DNA damage [77, 139]
Leaves boiled in waterBeverageLeafA 66-year-old female who has been diagnosed with cancer used to boil 10–12 dry leaves in water for 5–7 minutes, 8 oz PO daily at that timeHer metastatic breast cancer is still stable after 5 years on graviola and Xeloda after previously progressing on multiple lines of therapy [118]
MDA-MB-468———ExtractLeafDoses: 5, 25, 50, or 100 μg/mL; in vitro. In addition 200 mg/kg/35 week injected into the back of athymic mice in vivoInhibited EGFR-overexpression and EGFR mRNA expression. Induced cell cycle arrest at the G0/G1 phase. Induced apoptosis through caspase-3 activation. In vivo, it inhibited the growth of MDA-MB-468 tumors implanted in athymic mice (32% growth inhibition). It also significantly reduced the protein expression of EGFR, p-ERK, and p-EGFR in tumors [23]
MDAEthanolExtractLeafCytotoxic activity [93]
SKBR3EthanolExtractLeaf
T47DEthanolExtractFruitInduced cytotoxicity and apoptosis [22]
Bladder cancerECV-304EthanolExtractTwing0.1–10 mg/mL in vitro, and 0.5 g/kg into albino mice in vivo [96]Cytotoxic activity against cancer cells in vitro and within reduction of time reaction in vivo [96]
Prostate cancerPC-3Muricin J, K, or LAGEsLeafDose: 20 μg/mL (24 h)Antiproliferative activity against human cancer cells [29]
Annomuricin EAGELeafCytotoxic activity [16]
MuricapentocinAGELeaf
AnnohexocinAGELeafSignificant cytotoxic activity [34]
Annopentocin AAGELeafCytotoxic activity [32]
Annopentocin BAGELeaf
Annopentocin CAGELeaf
cis-Annomuricin-D-one + trans-annomuricin-D-oneAGEsLeaf
Murihexocin AAGELeafSignificant cytotoxic activity [15]
Murihexocin BAGELeaf
Murihexocin CAGEFruitCytotoxic activity [47]
Muricoreacin
Muricin MAGEfruitDose: 20 μg/mLAntiproliferative activities against human prostate cancer cells [30]
Muricin NAGEsLeaf
Muricenin
———WaterExtractLeafF344 male rats (≈200 g) were gavaged 30 mg/mL (10 rats) and 300 mg/mL (10 rats) and fed ad libitum alongside 10 control rats for two monthsReduced prostate size in vivo, possibly through apoptosis [21]
Colorectal cancerHT-29Annomuricin AAGELeafCytotoxic activity [17]
Annomuricin BAGELeaf
Annomuricin CAGELeaf—–—Cytotoxic activity [86]
Muricatocin C
Annomuricin EAGELeafDoses: 1, 2, 4, 8, and 16 μg/mL [25]; [16]; IC50: 5.72 ± 0.41 μg/mL (12 hr), 3.49 ± 0.22 μg/mL (24 hr), and 1.62 ± 0.24 μg/mL (48 hr) [25].Induced toxicity against cancer cells [16, 25]. Suppressed proliferation of cancer cells and induced lactate dehydrogenase leakage, cell cycle arrest at G1 phase, and apoptosis mediated through activation of caspases 3/7 and 9. Also induced a time-dependent upregulation of Bax and downregulation of Bcl-2 at both the mRNA and protein level [25]
MuricapentocinAGELeafCytotoxic activity [16]
AnnomutacinAGELeafCytotoxic activity [43]
(2,4-cis)-10R-Annonacin-A-one + (2,4-trans)-10R-annonacin-A-oneAGELeaf
AnnohexocinAGELeafSignificant cytotoxic activity [34]
Muricatocin AAGELeafCytotoxic activity [44]
Muricatocin BAGELeaf
Annopentocin AAGELeafCytotoxic activity [32]
Annopentocin BAGELeaf
Annopentocin CAGELeaf
cis-Annomuricin-D-one + trans-annomuricin-D-oneAGEsLeaf
Murihexocin AAGELeafSignificant cytotoxic activity [15]
Murihexocin BAGELeaf
Murihexocin CAGESeedCytotoxic activity [47]
MuricoreacinAGESeed
MuricatacinAGESeedCytotoxic activity [48]
IsoannonacinAGESeedCytotoxic activity [49]
Isoannonacin-10-oneAGESeed
GoniothalamicinAGESeed
GigantetrocinAGESeed and/or leaf
Gigantetrocin AAGESeedCytotoxic activity [50]
Muricatetrocin AAGESeed and/or leafCytotoxic activity [17, 50]
Muricatetrocin BAGESeed
Gigantetrocin BAGESeed
cis-AnnonacinAGESeedCytotoxic activity [85]
cis-Annonacin-10-oneAGESeed
cis-GoniothalamicinAGESeed
ArianacinAGELeaf
JavoricinAGELeaf
HexaneExtractLeafDoses: 10, 20, 40, and 80 μg/mL, (72 hr)Significantly reduced cell proliferation in cancer cells [26]
Ethyl acetateExtractLeafDoses in vitro: 10, 20, 40, and 80 μg/mL [26]; 0.62, 1.25, 2.5, 5, 10, 20, 40, and 80 μg/mL [25]; (72 hr) [26]. Doses in vivo: 250 or 500 mg/kg into male Sprague-Dawley rats [25].Induced significant cytotoxic effects, cell cycle arrest at G1 phase, and apoptosis. Treatment also caused excessive accumulation of ROS followed by disruption of MMP, cytochrome c leakage, and activation of the initiator and executioner caspases in cancer cells. In addition, it upregulated Bax and downregulated Bcl-2 proteins. Furthermore, treatment conspicuously blocked the migration and invasion of cancer cells [26]. In rats treated with azoxymethane to induce colorectal carcinogenesis. This extract reduced colonic aberrant crypt foci formation by 72.5% in vivo via downregulation of PCNA and Bcl-2 proteins and upregulation of Bax protein as well as an increase in the levels of enzymatic antioxidants and a decrease in the malondialdehyde level of the colon tissue homogenates, suggesting the suppression of lipid peroxidation [25]
MethanolExtractLeafDoses: 10, 20, 40, and 80 μg/mL and (72 hr)Significantly reduced the cell proliferation in cancer cells [26]
HCT-116HexaneExtractLeafDoses: 10, 20, 40, and 80 μg/mL and (72 hr)
Ethyl acetateExtractLeafDoses: 10, 20, 40, and 80 μg/mL and (72 hr)In cancer cells, induced significant cytotoxic effects, cell cycle arrest at the G1 phase, and apoptosis as well as excessive accumulation of ROS followed by disruption of MMP, cytochrome c leakage, and activation of the initiator and executioner caspases. It also upregulated Bax and downregulated Bcl-2 protein. Furthermore, treatment conspicuously blocked the migration and invasion of cancer cells [26]
MethanolExtractSeedDoses: 10, 20, 40, and 80 μg/mL and (72 hr)Significantly reduced cell proliferation in cancer cells [26]
HCT116 (p53+/+)MethanolExtractPericarpCytotoxic activity [24]
MethanolExtractLeaf
MethanolExtractSeed
HCT116 (p53/)MethanolExtractPericarp
MethanolExtractLeaf
MethanolExtractLeaf
———EthanolicExtractLeaf300 mg/kg into Wistar albino ratsShowed potent anticancer activity through apoptosis and reduction of aberrant crypt foci formation [20]
EthanolExtractLeaf100 mg/kg body weight/4 weeks are administrated into Wistar ratsIn a rat model of Cycas-induced colorectal carcinogenesis, protected against some early events as monitored by histology and protein expression [140]
COLO-20596% Ethanol [112] or ethanol soluble fraction leaf water extract contains 0.36% acetogenin (w/w) or 3.6 mg/g, and a 10 g water extract is equivalent to a 2 g ethanolic fraction [94].ExtractLeafDoses in vitro: 400, 200, 100, 50, 25, 12.5, 6.25, 3.125, and 1.5625 mg/L, (48 hr) [112]. Ex vivo, the colorectal cancer patients consumed either 300 mg of the extract, or maltose as a placebo, in the form of a capsule after breakfast [94].Enhanced proapoptotic caspase-3 marker activity [112]. Ex vivo and clinical studies showed higher cytotoxicity in the supplemented group compared with the placebo group [94]
DLD-1Ethanol soluble fraction leaf water extract contains 0.36% acetogenin (w/w) or 3.6 mg/g, and a 10 g water extract is equivalent to a 2 g ethanolic fraction.ExtractLeafPatients consumed either 300 mg of extract, or maltose as a placebo, in the form of a capsule after breakfast.Ex vivo and clinical studies showed higher cytotoxicity in the supplemented group compared with the placebo group [94]
HTC-8(+)-(3S,6S,7R,8S)-Periconone AFungal strain ExtractLeafDoses: 0.01–10 μmol/mlCytotoxic activity [38]
(−)-(1R,4R,6S,7S)-2-Caren-4,8-olideFungal strain ExtractLeaf
Lung cancerA549Annomuricin AAGELeafCytotoxic activity [17]
Annomuricin BAGELeaf
Annomuricin CAGELeaf—–—Cytotoxic activity [86]
Muricatocin CAGELeaf
Annomuricin EAGELeafCytotoxic activity [16]
MuricapentocinAGELeaf
AnnomutacinAGELeafCytotoxic activity [43]
(2,4-cis)-10R-Annonacin-A-one + (2,4-trans)-10R-annonacin-A-oneAGEsLeaf
AnnohexocinAGEsLeafSignificant cytotoxic activity [34]
Muricatocin AAGELeafCytotoxic activity [44]
Muricatocin BAGELeaf
Annopentocin AAGELeafCytotoxic activity [32]
Annopentocin BAGELeaf
Annopentocin CAGELeaf
cis-Annomuricin-D-one + trans-annomuricin-D-oneAGEsLeaf
Murihexocin AAGELeafSignificant cytotoxic activity [15]
Murihexocin BAGELeaf
Murihexocin CAGESeedCytotoxic activity [47]
MuricoreacinAGESeed
MuricatacinAGESeedCytotoxic activity [48]
IsoannonacinAGESeedCytotoxic activity [49]
Isoannonacin-10-oneAGESeed
GoniothalamicinAGESeed and/or leaf
GigantetrocinAGESeed and/or leaf
Gigantetrocin AAGESeedCytotoxic activity [17, 50]
Muricatetrocin AAGESeed and/or leaf
Muricatetrocin BAGESeed
Gigantetrocin BAGESeed
cis-AnnonacinAGESeedCytotoxic activity [85]
cis-Annonacin-10-oneAGESeed
cis-GoniothalamicinAGESeed
ArianacinAGELeafIC50 = 4.7 × 10−3μg/mL
JavoricinAGELeaf
Ethyl acetate componentExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL; IC50: 5.09 ± 0.41 μg/mL (72 hr)Selective cytotoxic effect against cancer cells and significant lactate dehydrogenase leakage and phosphatidylserine externalization demonstrated by fluorescence analysis. Treatment also elevated ROS formation, while attenuating MMP via upregulation of Bax and downregulation of Bcl-2. This was accompanied by cytochrome c release to the cytosol, which triggered activation of caspase-9 and caspase-3. These proapoptotic effects were accompanied by cell cycle arrest at the G0/G1 phase and suppression of NF-κB translocation from the cytoplasm to the nucleus [31]
HexaneExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL; Significantly reduced cell proliferation in cancer cells [31]
MethanolExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL;
(+)-(3S,6S,7R,8S)-Periconone AFungal strain ExtractLeafDoses: 0.01–10 μmol/mLCytotoxic activity [38]
(−)-(1R,4R,6S,7S)-2-Caren-4,8-olideFungal strain ExtractLeaf
H-460EthanolExtractTree/LeafCytotoxic activity [95]
Ethanol (95%)ExtractPericarpCytotoxic activity [45]
NCI-H292MethanolExtractPericarpIC50: 24.94 ± 0.74 μg/mLAntiproliferative and cytotoxic activities towards cancer cells [113]
Leukemia (hematological malignancies)U-937Annonacin AAGEPericarpDoses: 0.1, 0.46, and 1.0 mg/mLCytotoxic activity [46]
Annomuricin AAGEPericarp
MethanolExtractPericarp
HexaneExtractLeaf
Ethyle acetateExtractStem
Ethyle acetateExtractStemCytotoxic activity [131]
Ethyle acetateExtractStem and/or 28.1 ± 13.0 μg/mLCytotoxic activity [33]
MethanolExtractStem and/or 38.5 ± 8.6 μg/mL
HexaneExtractStem and/or 15.7 ± 5.1 μg/mL
K562EthanolExtractLeafDoses in vitro: 0.625 mg/mL, 1.25 mg/mL, 2.5 mg/mL, and 5.0 mg/mL [19]; 0.1–10 mg/mL [96]; [96]. Dose in vivo: 0.5 g/kg into albino mice [96].Showed cytotoxicity in vitro [19] and in vivo [96]. This was accompanied in vitro by significantly increased caspase-3 activity. Induction of apoptosis was confirmed by a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay [19]
HL-60EthanolExtractRootInduced apoptosis through loss of MMP and inhibited proliferation via G0/G1 cell cycle arrest [27]
EthanolExtractFruit/pericarp
EthanolExtractLeaf
CCRF-CEMMethanolExtractSeedInduced cytotoxic, apoptosis, and cell cycle arrest [24]
MethanolExtractLeaf
MethanolExtractSeed
CEM/ADR5000MethanolExtractPericarp
MethanolExtractLeaf
MethanolExtractLeaf