Potential Protective Effects of Antioxidants against Cyclophosphamide-Induced Nephrotoxicity

Ayza, Muluken Altaye; Zewdie, Kaleab Alemayehu; Yigzaw, Elias Fitsum; Ayele, Solomon Gashaw; Tesfaye, Bekalu Amare; Tafere, Gebrehiwot Gebremedhin; Abrha, Muzey Gebreyohannes

doi:https://doi.org/10.1155/2022/5096825

International Journal of Nephrology

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Abstract Introduction Conclusion Abbreviations Conflicts of Interest References Copyright Related Articles

Review Article | Open Access

Volume 2022 | Article ID 5096825 | https://doi.org/10.1155/2022/5096825

Potential Protective Effects of Antioxidants against Cyclophosphamide-Induced Nephrotoxicity

Muluken Altaye Ayza,¹Kaleab Alemayehu Zewdie,²Elias Fitsum Yigzaw,³Solomon Gashaw Ayele,⁴Bekalu Amare Tesfaye,²Gebrehiwot Gebremedhin Tafere,²and Muzey Gebreyohannes Abrha⁵

Academic Editor: Emmanuel Effa

Received20 Sept 2021

Revised11 Mar 2022

Accepted24 Mar 2022

Published16 Apr 2022

Abstract

Cyclophosphamide is an alkylating antineoplastic agent, and it is one of the most successful drugs with wide arrays of clinical activity. It has been in use for several types of cancer treatments and as an immunosuppressive agent for the management of autoimmune and immune-mediated diseases. Nowadays, its clinical use is limited due to various toxicities, including nephrotoxicity. Even though the mechanisms are not well understood, cyclophosphamide-induced nephrotoxicity is reported to be mediated through oxidative stress. This review focuses on the potential role of natural and plant-derived antioxidants in preventing cyclophosphamide-induced nephrotoxicity.

1. Introduction

Cyclophosphamide is an oxazaphosphorine, alkylating agent of the nitrogen mustard class with potent cytotoxic and immunosuppressive effects; first synthesized by Arnold and colleagues in 1958 [1–3]. It is widely used in the treatment of malignant tumors and autoimmune diseases including lupus, systemic sclerosis, and several types of vasculitides [4].

Cyclophosphamide is a biologically inactive prodrug that needs cytochrome-P450 mediated activation [5, 6]. The drug is first transformed into hydroxylated intermediates, which undergo breakdown to form the active compounds; phosphoramide mustard and acrolein (Figure 1). The final result of the reaction between phosphoramide mustard and DNA is cell death [7]. Another metabolite excreted in the urine is chloroacetaldehyde, which is formed during detoxification of cyclophosphamide. Acrolein and chloroacetaldehyde have been linked to various toxicities [8].

Cyclophosphamide is associated with various toxicities; with the cumulative dose being the principal risk factor [9]. Short-term effects include gastrointestinal effects (nausea, vomiting, anorexia, and diarrhea), myelosuppression, infection, alopecia, and hemorrhagic cystitis. Long-term risks include gonadal toxicity, teratogenicity, cardiotoxicity, and pulmonary toxicity [4, 9]. In addition to these, nephrotoxicity and hepatotoxicity can occur due to cyclophosphamide [10]. These multiple organ toxicities limited the clinical application of cyclophosphamide. One of the limiting effects of cyclophosphamide use is nephrotoxicity. Therefore, successful prevention of renal injury requires knowledge of pathogenic mechanisms and early interventions. This review focuses on the mechanisms and targets to ameliorate cyclophosphamide-induced nephrotoxicity.

2. Mechanisms and Role of Antioxidants in Cyclophosphamide-Induced Nephrotoxicity

Drugs are a common cause of kidney damage and contribute to morbidity and increased healthcare utilization [11, 12]. In patients with normal kidney function, nephrotoxicity can be considered if there is an increment in serum creatinine by ≥0.3 mg/dL within 48 h, increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days, and/or urine volume <0.5 mL/kg/h for 6 h [13].

Even though the mechanisms are not completely understood, one of the possible mechanisms of drug-induced nephrotoxicity is oxidative stress [14–16]. Oxidative stress occurs when there is excess oxygen radicals produced in cells, which could overpower the normal antioxidant capacity [17]. During cyclophosphamide metabolism and degradation of its metabolites, there is generation of reactive oxygen species (ROS) encompassing superoxide anions, hydroxyl radicals, and hydrogen peroxide [18]. The production of free radicals in turn leads to disruption of several signaling pathways including the inflammation pathways, which can lead to organ fibrosis [19]. In response to oxidative stress, c-Jun N-terminal kinase pathway is activated, which in turn phosphorylates c-Jun. Then, c-Jun induces transcription of genes that mediate inflammatory response like tumor necrosis factor alpha (TNF-a). The activation of JNK/c-Jun pathway by exposure to toxic agents/drugs or cellular stresses led to renal fibrosis through stimulation of both inflammation and apoptosis [20].

Levels of superoxide dismutase-1 (Cu/Zn-dependent enzyme) expression play an important role in cyclophosphamide-induced nephrotoxicity [21]. This is supported by the finding that the activity of the superoxide dismutase (SOD) was significantly reduced in the rat kidneys treated with cyclophosphamide. In addition, protein nitration, nitrotyrosine, and poly (ADP-ribose) polymerase activation and NAD depletion may play a critical role in the pathogenesis of cyclophosphamide-induced kidney damage [22].

Furthermore, the activities of antioxidant enzymes including, SOD, catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase are decreased after cyclophosphamide administration in rats. Treatment with amifostine, an organic thiophosphate compound, significantly protected kidney antioxidant parameters from changes induced by cyclophosphamide and, as a result, it prevented oxidative stress and peroxidative damage [18].

When cells are exposed to hydroxy-cyclophosphamide, a form of cyclophosphamide induces lipid peroxidation [23]. As reported by [24], rats treated with cyclophosphamide showed high biochemical parameters such as malondialdehyde (MDA) and low antioxidant activity (GSH) compared to the control group. Pretreatment with seleno L-methionine, an antioxidant compound, significantly prevented cyclophosphamide-induced lipid peroxidation in the kidney tissues [24].

Furthermore, treatment with gallic acid restored the enzymic and nonenzymic antioxidants and also attenuated cyclophosphamide-induced nephrotoxicity through free radical scavenging activity, anti-inflammatory, and improvement of antioxidant defense system [25]. Other compounds/extracts also prevented cyclophosphamide-induced kidney damage, including ozone therapy [26], hydroalcoholic extract of Capparis spinosa [27], methanolic extract of Curcuma caesia [28], Diallyl sulfide [29], Nigella sativa oil, and thymoquinone [30] (Table 1). Additionally, currently available drugs also show renoprotective effect (Table 2). These findings support the association between oxidative stress and cyclophosphamide-induced nephrotoxicity.

Even though, various studies reported the association between cyclophosphamide-induced nephrotoxicity and oxidative stress, [71] showed that pretreatment with glutamine (the precursor for glutathione synthesis) did not prevent cyclophosphamide-induced lipid peroxidation and renal damage. This might indicate the involvement of mechanisms other than oxidative stress, and/or oxidative stress might be the consequence and not the cause of cyclophosphamide-induced renal damage [71]. Cyclophosphamide-induced nephrotoxicity might be related to energy metabolism, amino acid metabolism, choline metabolism, and nucleotide metabolism. The nuclear magnetic resonance-based metabolomics approach revealed cyclophosphamide administration elevated choline and creatine levels, this might be due to inhibited choline metabolism. Hypoxanthine level was also decreased and this might be due to cyclophosphamide-induced disturbance in purine metabolism, which can imply the impairment of renal function [72].

3. Novel Clinical Biomarkers of Kidney Injury

Nephrotoxicity is one of the major reasons that drugs are withdrawn from the market, and it is a major concern to drug approval agencies and manufacturing companies [73]. Some of the currently available drugs possess nephrotoxic properties and traditionally been detected and defined by reduced urine output and elevated serum creatinine concentrations [74]. Serum creatinine, blood urea nitrogen (BUN), and urine output are standard measures of nephrotoxicity [75].

Serum biomarkers like serum creatinine and BUN may not be adequate to accurately detect kidney injury. They are suboptimal, because they merely reflect changes in the glomerular filtration rate; which is a nonspecific measure of proximal tubular injury, and it becomes apparent only after significant kidney damage. These biomarkers are insensitive, and they may allow drugs to pass preclinical safety criteria only to be found nephrotoxic in patients during clinical trials or postmarket clinical use. Additional noninvasive urinary biomarkers, like kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) might be important [76–78].

KIM-1 is a phosphatidylserine receptor on renal epithelial cells that recognize apoptotic cells, directing them to lysosomes and thereby converting the normal proximal tubule cell into a phagocyte. KIM-1 mRNA levels are elevated after initiation of kidney injury and outperformed serum creatinine, BUN, and urinary N-acetyl-β-D-glucosaminidase in rat models of kidney injury [79]. Unlike other kidney injury markers, urinary KIM-1 was found elevated at the early stages of the kidney injury in rats, and these elevations were sustained throughout the progression of cell injury to proliferation and regeneration [78].

Furthermore, fifteen female breast cancer patients, after treatment with adriamycin and cyclophosphamide showed a significant increase in KIM-1 level. Urinary KIM-1 can be a sensitive biomarker for the evaluation of early kidney injury in cancer patients on chemotherapy [80]. Human KIM-1, a soluble form, can be detected in the urine of patients with acute tubular necrosis, and it can be a useful biomarker for renal proximal tubule injury and facilitating early diagnosis [81].

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein, which is originally isolated from neutrophil secondary granules. It is freely filtered at the glomerulus and reabsorbed in the proximal tubule almost completely. Increased urinary excretion suggests proximal tubular damage with impaired reabsorption or increased primary synthesis and excretion by distal nephron segments [82]. It is one of the most promising renal markers [83]. In mice treated with cisplatin, NGAL is easily detected in the urine by western analysis within 3 hours of cisplatin administration in a dose and duration-dependent manner. But changes in urinary N-acetyl-β-D-glucosaminidase (NAG) or serum creatinine were not evident until 96 hours after cisplatin administration. NGAL can be an early and quantitative urinary biomarker for nephrotoxicity, and the most promising biomarker in clinical nephrology [84, 85].

Cyclophosphamide-induced cystitis with the tubulopathy character is expressed by the increased production and release of a fatty-acid binding protein (FABP) and osteopontin into the urine as markers reflecting acute kidney injury in rats [86]. FABP-4, predominantly expressed in adipocytes and macrophages, is increased in the urine of patients with a glomerular injury. It can have a potential value in the detection of early region-specific drug-induced kidney injury [87]. The level of FABP will increase after 4 hours of insult [82].

Another biomarker will be interleukin-18 (IL-18). It is a proinflammatory cytokine with 18 kDa molecular weight. One of the major sources of IL-18 production is a renal tubular cell. IL-18 is upregulated and increased during acute kidney injury [88]. It has been reported that IL-18 can be a promising marker of chronic renal injury in children after chemotherapy [89].

4. Hopes in the Management of Chemotherapy-Induced Nephrotoxicity

It has been reported that oxidative stress could be a key mechanism in cyclophosphamide-induced nephrotoxicity [51]. Thus, agents that can enhance host antioxidant defense mechanisms can be a promising target to ameliorate cyclophosphamide-induced nephrotoxicity [44]. Several studies reported that, enhancing the antioxidant and anti-inflammatory system can prevent nephrotoxicity (Table 1).

A study done by El-Shabrawy et al. [70] revealed that, tovaptan coadministration with cyclophosphamide significantly reduced lipid peroxidation marker, MDA, and proinflammatory cytokines. Due to tolvaptan coadministration, histopathological results also showed improvements of nephrotoxicity signs. As compared to cyclophosphamide-treated group, tolvaptan cotreatment significantly decreased the level of apoptosis markers as caspase-3 and Bax with increased expression of antiapoptotic Bcl-2 in renal tissue [70]. In addition, tolvaptan showed renoprotective effects in a Dahl hypertensive heart failure rats. In this study, renal fibrosis was found to be significantly inhibited in the tolvaptan-treated group of animals [90]. It can be concluded that, long-term therapy with tolvaptan may improve oxidative stress-induced renal dysfunction, podocyte injury, glomerulosclerosis, and inflammation [91].

A Chinese herbal complex Huaiqihuang, composed of Trametes robiniophila (Auriculariacaee), Lycium barbarum (Solanaceae), and Polygonatum sibiricum (Liliaceae) showed significant antioxidant, antiapoptosis, and anti-inflammatory activity and exhibits a therapeutic effect against renal diseases. Huaiqihuang showed protective effect against cyclophosphamide-induced nephrotoxicity in rats through decreasing the production of MDA, and increasing the activities of antioxidant enzymes including, CAT and SOD [92, 93].

An isoquinoline derivative alkaloid called Berberine proved to have an antioxidant and anti-inflammatory activity. Berberine showed protective effect against cyclophosphamide-induced renal injury through decreasing the level of kidney injury markers including, blood urea nitrogen, creatinine, kidney injury molecule-1 and increasing the level of antioxidants such as glutathione peroxidase, glutathione, superoxide dismutase, and catalase activities [94].

Through its antioxidant, antiapoptotic, and anti-inflammatory properties, berberine also exerted nephrprotective effects against gentamicin-induced nephrotoxicity in rats [95]. Berberine also resulted in an ameliorative effect against cisplatin-induced nephrotoxicity in rats, through enhancing the antioxidant capacity and reducing the oxidative stress markers in the renal tissue [96]. It can be concluded that, berberine might be a good candidate for nephroprotective effect and further studies need to be recommended.

Furthermore, in a randomized control trial, advanced ovarian cancer patients pretreated with amifostine revealed reduced cumulative hematologic, renal, and neurologic toxicities associated with the cyclophosphamide-regimen, with no reduction in antitumor efficacy [97]. Amifostine (ethyol or WR2721) is an FDA-approved sulfhydryl compound that is administered to patients as a cytoprotective treatment before chemotherapy. It protects normal cells by scavenging free radicals and through hydrogen donation to reactive oxygen species and regulating the transcription of genes involved in apoptosis, cell cycle, and DNA repair [98, 99]. In addition, amifostine resulted in the inhibition of oxidative stress and lipid peroxidation in the kidneys of cyclophosphamide-treated rats. Collectively, amifostine is reported to prevent cyclophosphamide-induced renal injury and dysfunction [18]. These and other antioxidants have the ability to diminish free radical formation and promote endogenous antioxidant enzyme activity; they can be a possible source for nephroprotective agents in the future.

5. Conclusion

Cyclophosphamide is an alkylating agent widely used for the treatment of cancer, and it has been used to treat severe manifestations of autoimmune inflammatory diseases, including systemic vasculitis, systemic lupus erythematosus, and systemic sclerosis. However, cyclophosphamide is associated with renal dysfunction, and its clinical use is limited due to various toxicities. Several natural and plant-based antioxidants have shown an important and promising nephroprotective activity in preclinical studies, and they might be an effective source for nephroprotctive agents. In addition to oxidative stress, there might be an involvement of other mechanisms related with energy, amino acid, choline, and nucleotide metabolism pathwys; worth considering. Further investigations are recommended to understand their safety and efficacy profile on a clinical basis. Translational clinical researches should be considered on those found to be safe and effective in preclinical studies.

Abbreviations

CAT:	Catalase
CP:	Cyclophosphamide
CVDs:	Cardiovascular diseases
GSH:	Glutathione
GSH-Px:	Glutathione peroxidase
KIM-1:	Kidney injury molecule-1
NGAL:	Neutrophil gelatinase-associated lipocalin
ROS:	Reactive oxygen species.

Conflicts of Interest

The authors declare no conflicts of interest.

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