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. Author manuscript; available in PMC: 2022 Mar 29.
Published in final edited form as: Adv Cancer Res. 2021 Apr 28;152:305–327. doi: 10.1016/bs.acr.2021.03.008

Cisplatin chemotherapy and renal function

Jie Zhang a,*, Zhi-wei Ye a, Kenneth D Tew a, Danyelle M Townsend b,*
PMCID: PMC8963537  NIHMSID: NIHMS1742440  PMID: 34353441

Abstract

Cisplatin has been a mainstay of cancer chemotherapy since the 1970s. Despite its broad anticancer potential, its clinical use has regularly been constrained by kidney toxicities. This review details those biochemical pathways and metabolic conversions that underlie the kidney toxicities. A wide range of redox events contribute to the eventual physiological consequences of drug activities.

1. Introduction

Cisplatin is a square–planar complex with two labile chloride (Cl) ion ligands and two relative inert ammonia (NH3) ligands coordinated to the central platinum (Pt) atom in a cis configuration (Fig. 1A). The drug was first approved as an antineoplastic agent in 1978 and remains an important and effective therapy today for the treatment of various cancers including bladder, breast, cervical, esophageal, head and neck, ovarian, prostate, small and non-small cell lung, stomach, testicular cancers, Hodgkin’s and non-Hodgkin’s lymphomas, melanoma, mesothelioma, multiple myeloma, neuroblastoma, and sarcomas (Koepsell, Lips, & Volk, 2007). When cisplatin enters the cells, the low intracellular chloride concentration can lead to the dissociation of the chlorides resulting in the formation of monoaquo and diaquo complexes, and the hydrolyzed product is a potent electrophile that can react with the purine bases on the DNA. The various adducts and crosslinks induced by cisplatin have a multitude of effects including DNA unwinding, DNA bending, replication inhibition, and transcription inhibition, which can further cause DNA strand breaks, impaired cell division and apoptotic cell death (Dasari & Tchounwou, 2014; Manohar & Leung, 2018).

Fig. 1.

Fig. 1

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Schematic representation of cisplatin renal uptake and excretion. (A) Chemical structure of cisplatin. (B) Transporters involved in active tubular secretion of cisplatin into urine. Cisplatin is removed from the circulating blood and enters the proximal tubule cells either by passive diffusion or basolaterally expressed OCT2 and Ctr1. Cisplatin is then removed into the tubular lumen by apically expressed MATE1. OCT2, organic cation transporter 2; Ctr1, copper transporter 1; MATE1, multidrug and toxin extrusion transporter 1.

Although cisplatin has been on the market for more than 40 years, we are still struggling with its severe dose-limiting side effects, especially nephrotoxicity, which can be dose limiting in 30–40% of patients (Ridzuan et al., 2019). The clinical signs of kidney damage are a decrease in renal plasma flow and glomerular filtration rate (GFR) and an increase in blood urea nitrogen (BUN) and serum creatinine (Cr) concentrations (Volarevic et al., 2019). Cisplatin nephrotoxicity can present in a number of ways, e.g., acute kidney injury, hypomagnesemia, hypocalcemia, hyperuricemia, distal renal tubular acidosis, proximal tubular dysfunction, and chronic renal failure. Among these, the most serious and more common presentations is acute kidney injury, which occurs in 20–30% of patients (Gomez-Sierra, Eugenio-Perez, Sanchez-Chinchillas, & Pedraza-Chaverri, 2018). Primary approaches to protect from cisplatin-induced nephrotoxicity are based on avoiding extreme exposure of the kidneys to the drug. This is managed primarily by hydration with saline infusion and concomitant administration of mannitol, furosemide or magnesium, monitoring of renal function by serum Cr clearance, and decreasing cisplatin doses upon manifestation of renal dysfunction. However, even with aggressive hydration, renal toxicity occurs (Hakiminia, Goudarzi, & Moghaddas, 2019; Miller, Tadagavadi, Ramesh, & Reeves, 2010). Therefore, more effective preventative strategies without attenuation of tumoricidal activity need to be developed.

The development of effective tumor interventions with reduced nephrotoxicity relies heavily on understanding the molecular pathophysiology of cisplatin-induced nephrotoxicity. Cisplatin kills dividing cells by forming platinum-DNA crosslinks that prevent DNA synthesis and results in cell death. However, proximal tubular cells are not replicating, suggesting an alternative mechanism of toxicity (Tanase et al., 2019). The cellular process of nephrotoxicity can be attributed to local accumulation of cisplatin inside the renal proximal tubule by membrane transportation, and intracellular conversion of the drug into toxic metabolites (Hakiminia et al., 2019; Hanigan, Gallagher, & Taylor, 1996). Among the reported mechanisms of cisplatin nephrotoxicity are dysregulation of oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, inflammatory responses (macrophage/monocyte infiltration into renal cortex and medulla), apoptosis, necrosis and autophagy (Hanigan & Devarajan, 2003). The roles of these factors seem to be closely related. Oxidative stress is one of the best characterized mechanisms for cisplatin nephrotoxicity and will be discussed later in this review.

2. Cisplatin renal uptake and excretion

During glomerular filtration and tubular secretion, cisplatin is markedly accumulated in the kidney, and the concentration in proximal tubules is about five times greater than that in blood. Accordingly, even non-toxic serum concentrations of cisplatin may reach toxic levels in the kidney, resulting in impaired renal function due to the severe injury of S3 segment of proximal tubules (Dasari & Tchounwou, 2014; Holditch, Brown, Lombardi, Nguyen, & Edelstein, 2019). Cisplatin can enter the renal tubular cells by either passive diffusion or active transport. Previous studies have indicated that movement of cisplatin through the renal tubular cells occurs in a basolateral to apical direction (Gomez-Sierra et al., 2018). Specifically, cisplatin is removed from the circulating blood and enters renal tubular cells by the actions of basolaterally expressed transporters such as organic cation transporter 2 (OCT2, the main OCT in human kidney (Yao, Panichpisal, Kurtzman, & Nugent, 2007)) and, to a lesser extent, copper transporter 1 (Ctr1). It is then removed into the tubular lumen by apically expressed multidrug and toxin extrusion transporter 1 (MATE1) (Ridzuan et al., 2019) (Fig. 1B). In line with these observations, cisplatin nephrotoxicity is positively correlated with OCT2 and Ctr1 expression, and negatively correlated with MATE1.

OCT2 is most strongly expressed in the kidney and is localized to the basolateral membrane of renal proximal tubular cells (George, You, Joy, & Aleksunes, 2017; Yao et al., 2007). Notably, reduced cisplatin nephrotoxicity has been observed in vivo in cisplatin-treated (Koepsell et al., 2007) OCT2 knockout mice (Ciarimboli et al., 2010; Filipski, Mathijssen, Mikkelsen, Schinkel, & Sparreboom, 2009) or wild-type mice pretreated with cimetidine, a pharmacological inhibitor of OCT2 (Ciarimboli et al., 2010; Manohar & Leung, 2018) female rats whose OCT2 expression levels are much lower than those in males (Dasari & Tchounwou, 2014; Nematbakhsh et al., 2013; Urakami et al., 1999) cancer patients with a non-synonymous single-nucleotide polymorphism in the OCT2 gene SLC22A2 (rs316019) (Filipski et al., 2009; Ridzuan et al., 2019) cancer patients who received prehydration with magnesium which is assumed to down-regulate OCT2 levels (Muraki et al., 2012; Oka et al., 2014; Volarevic et al., 2019; Yamamoto et al., 2015; Yokoo et al., 2009) cancer patients who received cimetidine and verapamil (a calcium entry blocker) along with cisplatin (Sleijfer et al., 1987).

Ctr1 is highly expressed in adult kidney and the protein is localized on the basolateral side of both proximal and distal tubular cells (Pabla, Murphy, Liu, & Dong, 2009). In vitro downregulation of Ctr1 in kidney cells suppresses both cisplatin uptake and cytotoxicity, including cell death by both apoptosis and necrosis (Pabla et al., 2009). However, the role of Ctr1 in cisplatin nephrotoxicity has not yet been examined in vivo. Considering the crucial role of Ctr1 for cisplatin to enter the tumor cells (Holzer et al., 2004), concern has been raised that targeting this transporter for a renoprotective strategy may affect the antitumor effects of the drug. Thus, it is important to use tumor bearing in vivo models to determine the effects of therapies targeting cisplatin transporters on the cancers as well as renoprotection.

MATE1 is highly expressed in the brush-border membrane of renal proximal tubules and mediates the efflux of cisplatin from the renal epithelial cells into the urine. Higher renal accumulation of cisplatin, lower survival, and higher creatinine and BUN levels have been observed in cisplatin–treated MATE1 knockout mice or wild-type mice pretreated with pyrimethamine, a selective MATE inhibitor, suggesting the fundamental role of MATE1 in controlling the nephrotoxicity (Nakamura, Yonezawa, Hashimoto, Katsura, & Inui, 2010). Inversely, less accumulation of cisplatin in renal tissue has been found in cisplatin-treated kinin B1 receptor knockout mice or wild-type mice pretreated with a kinin B1 receptor antagonist R-715. Kinin B1 receptor deletion and blockage resulted in higher expression of MATE1 and consequently protected against cisplatin-induced acute kidney injury (Estrela et al., 2017). In humans the renal clearance of cisplatin exceeds the glomerular filtration rate, indicating that cisplatin is secreted across renal tubular cells (Nakamura et al., 2010). Additional studies are required to reveal the contribution of MATE family to the renal handling of cisplatin in humans.

3. Bioactivation of cisplatin in the kidney

Cisplatin undergoes metabolic activation in the kidney to a more potent toxin (Fig. 2). The first step of cisplatin metabolism is the formation of a glutathione (GSH)-conjugate, in which one of the chloride ions of cisplatin is replaced by the sulfur moiety of GSH (Townsend, Marto, Deng, Macdonald, & Hanigan, 2003). Buthionine sulfoximine, which depletes endogenous GSH by inhibiting GSH synthesis, has been shown to protect against cisplatin nephrotoxicity in rats (Mayer, Lee, & Cockett, 1987). GSH-conjugates are generally formed in the liver, which contains the highest level of glutathione-S-transferase (GST) (Hanigan, Gallagher, Taylor, & Large, 1994), and the conjugates are excreted from the cell into the serum or the bile via the multidrug-resistance-associated protein transporters (Homolya, Varadi, & Sarkadi, 2003; Zhang et al., 2014). Pharmacological inhibition of GST by ketoprofen has been shown to protect against cisplatin nephrotoxicity in rat (Sadzuka, Shimizu, Takino, & Hirota, 1994). However, the specific GST isoforms that may catalyze the formation of GSH-conjugate in the activation of cisplatin to a renal toxin have not been identified, nor has the location where this conjugate is formed in the body been determined. GstP1/P2 wild-type males had more extensive renal damage than either female wild-type or GstP1/P2 null mice (Townsend, Tew, He, King, & Hanigan, 2009). Wild-type males have ~10-fold higher levels of GSTP expression in the liver than females, and the liver is the only organ which shows gender difference of GSTP expression (Knight, Choudhuri, & Klaassen, 2007), suggesting that higher levels of GSTP expression in the liver may enhance the formation of cisplatin-GSH-conjugate that is metabolized to renal toxins. Contradictorily, a recent study indicated that cisplatin is not a substrate for GSTP as the GSH-adduct formation is not affected by human GSTP1–1. However, the conclusion was drawn based on the in vitro incubation of a high concentration of cisplatin (1 mM) with GSH (2mM) (De Luca et al., 2019). While the enzyme can catalyze GSH conjugation, other properties so far ascribed to GSTP include chaperone functions, regulation of nitric oxide pathways, regulation of a variety of kinase signaling pathways, participation in the forward reaction of protein S-glutathionylation and maintenance of cellular redox homeostasis (Tew et al., 2011; Zhang et al., 2014). Considering the pleiotropic functions of GSTP, its role in the cisplatin nephrotoxicity remains to be established.

Fig. 2.

Fig. 2

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Bioactivation of cisplatin to a nephrotoxin. The first step of cisplatin metabolism is the formation of a GSH-conjugate catalyzed by GST. As the cisplatin-GSH-conjugate passes through the kidney, it is cleaved by GGT to a cysteinyl-glycine-conjugate, which is further converted to a cysteine-conjugate by APN. GGT and APN are both plasma membrane-bound enzymes with the catalytic domain exposed to the extracellular surface. As the cisplatin-cysteine-conjugate enters the proximal tubular epithelial cell, it is further metabolized by a pyridoxal 5′-phosphate-dependent enzyme, CCBL, to a highly reactive and nephrotoxic thiol that would bind to proteins. The cytosolic glutamine transaminase K and especially the mitochondrial aspartate aminotransferase are the major CCBLs involved in the bioactiviation of cisplatin-cysteine-conjugate. GST, glutathione transferase; GGT, gamma glutamyl transpeptidase; APN, aminopeptidase N; CCBL, cysteine-S-conjugate beta-lyase.

As the cisplatin-GSH-conjugate passes through the kidney by the multidrug resistance-associated protein 2, it is cleaved by gamma glutamyl transpeptidase (GGT) to a cysteinyl-glycine-conjugate, which is further converted to a cysteine-conjugate by aminopeptidase N (APN). Both GGT (Hanigan & Pitot, 1985) and APN (Jardinaud et al., 2004) are abundantly expressed on the luminal surface of the renal proximal tubule epithelial cells, and both reactions happen extracellularly. GGT is a plasma membrane-bound enzyme with the active side directed into the extracellular space, and it is the first enzyme in the metabolic pathway for the activation of cisplatin-GSH-conjugate. Kidney has the highest GGT activity (Hanigan & Pitot, 1985), and the activity of GGT has been shown to be essential for the cisplatin nephrotoxicity. Pretreatment with GGT inhibitor acivicin in rats and mice, or knockout of Ggt genes in mice significantly protected the animals from the cisplatin-induced renal toxicity without reducing platinum concentration in the kidney. The protective effect was confirmed by BUN, and Cr levels, and quantitative histologic analysis (Hanigan et al., 1994; Hanigan et al., 2001; Tanase et al., 2019; Townsend & Hanigan, 2002). In line with these results, in vitro data showed that pharmacological inhibition of GGT by OU749 or acivicin in renal proximal tubular epithelial cells (RPTEC-SV40 or LLC-PK1) eliminated the toxicities of cisplatin and cisplatin-GSH-conjugate, but had no significant effect on the toxicity of cisplatin-cysteinyl-glycine-conjugate (Fliedl et al., 2014; Townsend, Deng, Zhang, Lapus, & Hanigan, 2003). In addition, high doses of GSH have been found to reduce nephrotoxicity In vivo (Hanigan et al., 1994), but the biochemical mechanism of this protective action is not fully understood. GSH is the major physiological substrate for GGT (Hanigan & Ricketts, 1993). High concentration of GSH may protect against cisplatin nephrotoxicity by serving as a competitive inhibitor of GGT activity (Hanigan et al., 1994). Consistently, NOV-002, a mimetic of glutathione disulfide (GSSG), has been shown to be an effective protector against cisplatin-induced kidney toxicity in mice possibly through its ability to act as a competitive substrate for GGT ( Jenderny, Lin, Garrett, Tew, & Townsend, 2010). Intriguingly, GGT-negative prostate cancer xenografts grew at less than twice the rate of the GGT-positive tumors, and were significantly more sensitive to cisplatin toxicity than GGT-positive tumors, suggesting that GGT inhibition may reduce the nephrotoxicity of cisplatin, yet enhance its antitumor effect (Hanigan, Gallagher, Townsend, & Gabarra, 1999). Taken together, GGT was considered as a good target for the attenuation of cisplatin nephrotoxicity. GSH is the most abundant cellular antioxidant preventing protein thiols from oxidation either directly or indirectly through catalytic systems such as glutathione peroxidases (Ye, Zhang, Townsend, & Tew, 2015; Zhang, Ye, Singh, Townsend, & Tew, 2018). NOV-002 was shown to decrease GSH/GSSG ratio, increase oxidative stress and increase S-glutathionylation of protein thiols, thus influences multiple redox pathways critical to the maintenance of cell viability (Townsend et al., 2008; Townsend, Pazoles, & Tew, 2008; Townsend & Tew, 2009; Uys et al., 2010). The specific role of thiol homeostasis in the cisplatin nephrotoxicity remains to be established.

APN, like GGT, is a membrane associated enzyme with the catalytic domain exposed to the extracellular surface, and is the key enzyme immediately downstream in the GGT toxification pathway (Hausheer et al., 2011). Many peptides and small molecules, including GSH and cysteinyl-glycine dipeptides, have been shown to inhibit APN (Bauvois & Dauzonne, 2006; Hausheer et al., 2011). Accordingly, in human proximal tubular epithelial HK-2 cells, both GSH and cysteinyl-glycine have been shown to be able to ameliorate cisplatin toxicity (Paolicchi et al., 2003). In addition, Hausheer and colleagues proposed that the cisplatin nephroprotection effect of the disulfide BNP7787 (disodium 2,2′-dithio-bis ethane sulfonate, dimesna, Tavocept™) could result from the inhibition of GGT activity, mediated by BNP7787-dervied mesna-disulfide heteroconjugates that contain a terminal gamma-glutamate moiety (e.g., mesna-GSH, and mesna-cyteinyl-glutamate) (Hausheer et al., 2010), and/or the inhibition of APN activity by mesnacysteine, mesna-GSH, and mesna-cysteinyl-glycine (Hausheer et al., 2011). BNP7787 can act as a pharmacological surrogate/modulator of physiological thiols and disulfides and its active pharmacophore, mesna, was able to attach to cisplatin rendering it non-toxic since the mesna-cisplatin conjugate is not the substrate for GGT toxification (Hausheer et al., 2010). Due to the capacity to prevent the formation of a GSH-conjugates, thiol-generating agents have been tested as nephroprotective drugs in cisplatin-treated patients. However, their clinical values have been limited by the unwanted tumor protecting effect as well as their own intrinsic toxicities. The only agent that is approved for prevention of cisplatin nephrotoxicity in patients with non-small cell lung cancer and advanced ovarian cancer is amifostine (ethanethiol, 2-[(3-aminopropyl) amino] dihydrogen phosphate ester). However, its administration is associated with several potentially serious side effects, including ototoxicity and hypotension (Hausheer et al., 2011; Ridzuan et al., 2019).

As the cisplatin-cysteine-conjugate enters the proximal tubular epithelial cells, it is further metabolized by a pyridoxal 5′-phosphate (PLP)-dependent enzyme, cysteine-S-conjugate beta-lyase (CCBL), to a highly reactive and nephrotoxic thiol that would bind to proteins. Mammalian tissues contain at least eleven PLP-dependent enzymes with CCBL activity (Cooper et al., 2011; Cooper & Pinto, 2006). Among them, overexpression of the cytosolic glutamine transaminase K and the mitochondrial aspartate aminotransferase (mitAAT) has been shown to significantly increase the cisplatin toxicity in confluent LLC-PK1 cells (Zhang et al., 2006; Zhang & Hanigan, 2003). Consistently, inhibition of the CCBL activities by aminooxyacetic acid (AOAA), a general inhibitor of PLP-containing enzymes, led to amelioration of cisplatin nephrotoxicity both in vitro and in vivo (Townsend, Deng, et al., 2003; Townsend & Hanigan, 2002; Zhang et al., 2006). In the kidney, the proximal tubules are targeted by cisplatin and mitochondria are especially vulnerable. In mice pretreated with AOAA, platination of renal proteins was decreased in mitochondria, but not in the cytosol, suggesting that mitAAT is a major CCBL involved in the bioactiviation of cisplatin-cysteine-conjugate. The highly reactive cisplatin-thiol compound rapidly binds to the sulfhydryl moieties of the proteins in proximity in mitochondria, such as alpha-ketoglutarate dehydrogenase and to a lesser extent aconitase, and the deactivation of these proteins may contribute to the cisplatin-induced mitochondrial dysfunction of energy metabolism in kidney cells (Cooper et al., 2011; Zhang et al., 2006). Unlike GGT and APN, mitAAT is widely distributed among various organs. Liver, heart, brain, kidney and skeletal muscles exhibit high levels of mitAspAT activity (Parli, Godfrey, & Ross, 1987). Therefore, the nephrotoxicity of cisplatin cannot be explained on the basis of the tissue expression of this enzyme.

4. Oxidative stress in cisplatin-induced nephrotoxicity

Oxidative stress is a hallmark of cisplatin-induced nephrotoxicity, and it is characterized as an imbalance between the production and destruction of reactive oxygen species (ROS), the latter is regulated by antioxidant defenses. The term ROS refers to a number of chemically reactive molecules derived from O2, and the most common and biologically important ROS are O2− (superoxide anions), H2O2 (hydrogen peroxide) and OH• (hydroxyl radicals). Of these, OH• is invariably toxic, O2− is a byproduct of mitochondrial oxidation reactions and H2O2 has evolved into an important intermediary signaling molecule. Primary sites of intracellular ROS include the mitochondrial electron transport chain (ETC), ER and NADPH oxidase (NOX) complex. Antioxidant enzymes include superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), peroxiredoxin (Prx), GST, glutaredoxin (Grx), thioredoxin (Trx), and thioredoxin reductase (TrxR). Low molecular weight cofactor, such as GSH and NADPH also play an important role in the antioxidant defense. In addition, selenium has a critical role in maintaining antioxidant defenses (Ye et al., 2015).

A substantial source of ROS production is from mitochondria, the organelle responsible for producing ATP. Cisplatin accumulation in mitochondria is favored as the positively charged hydrolysis product of cisplatin is preferentially attracted by the negatively charged mitochondria, and this phenomenon may partly explain the particular sensitivity of the renal proximal tubule to cisplatin toxicity, as this segment exhibits one of the highest densities of mitochondria in the kidney (Gomez-Sierra et al., 2018). Following cisplatin administration, mitochondrial ROS levels significantly increase through different mechanisms which contribute to nephrotoxicity (Hanigan & Devarajan, 2003). First of all, cisplatin, as an electrophile, can directly disrupt the action of mitochondrial complexes, leading to increased production of ROS. In addition, recent studies have focused on the indirect effects of cisplatin on mitochondrial ROS generation. Mitochondria require narrow parameters to maintain their function, and reduction of mitochondrial function would result in increased ROS production and decreased ATP production. For example, cisplatin binds to mitochondrial DNA which blocks transcription, thus leading to decreased ETC protein expression, impaired respiration, and enhanced ROS generation (Marullo et al., 2013). Increased ROS formation promotes cell death and further damages respiratory complexes, thus enhancing cellular damage (Volarevic et al., 2019; Waseem &Parvez, 2013). In addition, cisplatin disrupts mitochondrial bioenergetics through inhibition of PPARα-mediated expression of genes involved in fatty acid metabolism. Fatty acid oxidation is the major source of energy for the renal proximal tubule, and treatment of PPARα agonists has been reported to reduce cisplatin nephrotoxicity in vivo (Gomez-Sierra et al., 2018). Another important effect of cisplatin on mitochondrial bioenergetics is the blockage of mitochondrial glutamate oxaloacetate transaminase (Ozaki et al., 2013), which catalyzes the conversion of glutamate and oxaloacetate with aspartate and α-ketoglutarate, and plays an important role in NADH (the main electron donor for oxidative phosphorylation) entry into the mitochondria. Cisplatin is able to inhibit mitochondrial transcription factor A by upregulating miR-709 (Guo et al., 2018), and inhibit the nuclear translocation of estrogen receptor alpha, an orphan nuclear receptor that acts as a transcription factor to regulate the transcription of genes required for mitochondrial biogenesis and oxidative phosphorylation (Tsushida et al., 2018). Furthermore, cisplatin increases mitochondrial ROS accumulation by decreasing mitochondrial GSH levels, which may result from GSH oxidation or decreased GR activity (Volarevic et al., 2019).

Cisplatin also stimulates ROS formation mediated by NOX enzymes. O2− production significantly increased in glomeruli and proximal tubules after cisplatin treatment, and the enhancement has been shown to be associated with the increased expression of the NOX subunits gp91 (phox) and p47 (phox). In agreement with this phenomenon, the enhanced O2− production has been shown to be prevented by the NOX2 selective inhibitor diphenylene iodonium (Trujillo et al., 2015). Among NOX1—5, NOX1 was found to have a nuclear location with plasma membrane and cytoplasmic distribution, NOX2, 3, and 5 are detected at the plasma membrane, and NOX4 has been identified in nucleus and ER (Brown & Griendling, 2009). NOX4 is highly expressed in the kidney and its expression is significantly upregulated in cisplatin-induced acute kidney injury model. NOX4 aggravates cisplatin-induced nephrotoxicity by promoting ROS-mediated programmed cell death and inflammation, and disruption of NOX4 has been shown to contribute to renal function recovery and kidney damage relief (Meng et al., 2018).

Cytochrome P450 (CYP) is an ER-anchored family of heme-containing monooxygenases that can produce O2− and H2O2, and can cause the release of catalytic iron, and through Fenton reactions to the generation of potent oxidants. Among the isoforms, CYP2E1 has been identified and localized to the kidney proximal tubules. CYP2E1 null mice demonstrated marked functional and histological protection against cisplatin-induced renal injury as compared to wild-type mice (Liu & Baliga, 2003). In addition, renal proximal tubular epithelial cells that were transfected with anti-caspase 12 (an ER-specific caspase) antibody significantly attenuated cisplatin-induced apoptosis. It is proposed that the interaction of cisplatin with CYP2E1 promotes the generation of ROS leading to activation of caspase 12 and subsequent apoptosis. (Liu & Baliga, 2005; Quintanilha et al., 2017). Oxidative stress is widely known to be related to ER stress as ROS may disrupt proper protein folding (Cao & Kaufman, 2014). Indeed, cisplatin has been shown to induce ER stress and unfolded protein response which triggers cell death (Peyrou, Hanna, & Cribb, 2007). ER stress in turn further increases ROS production in ER, mitochondria, and NOX system. Oxidative protein folding is another important resource of ROS production in ER. After accepting electrons from protein disulfide isomerases, ER oxidoreductase 1 transfers the electrons to O2 and produces H2O2 in the ER lumen (Ye et al., 2015). In addition, ER stress promotes Ca2+ release from ER into cytosol. Ca2+ is taken by mitochondria, resulting in mitochondrial transition pore opening, cytochrome c release, improper respiration and enhanced ROS production (Cao & Kaufman, 2014). Moreover, cytosolic Ca2+ is able to activate calcium/calmodulin-dependent kinase II, which stimulates NOX-mediated ROS production (Pandey, Gratton, Rafikov, Black, & Fulton, 2011).

As evidenced above, cisplatin, through multiple pathways, promotes ROS production, and the main downstream consequence of uncontrolled ROS accumulation is cell death. ROS play a central role in apoptosis induction mediated by intrinsic mitochondrial dysfunction, ER stress, and extrinsic death receptor activation. In addition to the processes described above, cisplatin-induced ROS has been reported to be involved in the activation of p53, the master regulator of apoptosis, leading to enhanced expression of Bax and PUMA (p53 upregulated modulator of apoptosis, also known as Bcl-2-binding component 3), which participate in mitochondrial pore formation and subsequent cytochrome c release, as well as upregulation of genes that encode for the extrinsic apoptosis protein Fas, FasL and TNFα (tumor necrosis factor-alpha). The latter is also the main driver for the development of renal inflammation after cisplatin treatment (Volarevic et al., 2019). ROS have also been proposed to promote cytochrome c release by direct oxidation of cardiolipin, a mitochondrial phospholipid that binds to cytochrome c (Santos et al., 2008). Therefore, oxidative stress is one of the best characterized mechanisms for cisplatin nephrotoxicity and is closely related with other mechanisms of cisplatin nephrotoxicity, such as mitochondrial dysfunction, ER stress, inflammatory responses, and apoptosis (Fig. 3).

Fig. 3.

Fig. 3

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Summary of the major pathways involved in cisplatin nephrotoxicity. Cisplatin, through multiple pathways, promotes ROS production in mitochondria, ER and NOX system, and the main downstream consequence of uncontrolled ROS accumulation (oxidative stress) is cell death. Oxidative stress is one of the best characterized mechanisms for cisplatin nephrotoxicity and is closely related with other mechanisms of cisplatin nephrotoxicity. For example, oxidative stress plays a central role in apoptosis induction mediated by intrinsic mitochondrial dysfunction, and ER stress. In addition, cisplatin-induced oxidative stress has been reported to be involved in the activation of p53, leading to enhanced expression of Bax and PUMA, which participate in mitochondrial pore formation and subsequent cytochrome c release, as well as upregulation of genes that encode for the extrinsic apoptosis protein Fas, FasL and TNFα, the latter is also the main driver for the development of renal inflammation after cisplatin treatment. AIF, apoptosis inducing factor; DAMPs, danger-associated molecular pattern molecules; ER, endoplasmic reticulum; PUMA, p53 upregulated modulator of apoptosis, also known as Bcl-2-binding component 3; TLR, toll-like receptor; TNFα, tumor necrosis factor-alpha.

5. Antioxidants against cisplatin-induced nephrotoxicity

Unchecked production of ROS is a major contributor to cisplatin-induced nephrotoxicity, making antioxidant-based therapies a popular choice for therapeutic intervention. Several natural antioxidant compounds have been shown to protect against cisplatin-induced kidney toxicity (Dasari & Tchounwou, 2014). Both in vivo and in vitro studies demonstrated that extracts from different types of ginseng (American ginseng (Ma et al., 2017; Ma et al., 2017), Chinese ginseng (Liu et al., 2014), Korean black ginseng (Han et al., 2016; Jung, An, Eom, Kang, & Kim, 2017), and Korean red ginseng (Kim et al., 2014)) and active constituents of ginseng (ginsenosides (Baek, Shin, Kim, Chang, & Park, 2017; Li et al., 2016), pseudoginsenoside (Wang et al., 2014) and anthocyanin (Qi et al., 2017)) are able to protect against cisplatin-induced nephrotoxicity by restoring redox balance and exerting anti-apoptotic and anti-inflammatory effect, as evidenced by decreased ROS generation and lipid peroxidation, increased GSH and antioxidant enzyme (catalase and SOD) levels, restored Bcl2: Bax ratio, and suppressed activation of p53, caspase 3 and 9, NFκB, IL1β, COX2 and iNOS. Similarly, licorice extract and its active components (glycyrrhizic acid, 18β-glycyrrhizic acid, and isoliquiritigenin) (Arjumand & Sultana, 2011; Ju et al., 2017; Patricia Moreno-Londono, Bello-Alvarez, & Pedraza-Chaverri, 2017; Wu, Chen, & Yen, 2015), curcumin (the most active and major phytochemical found in the rhizome of turmeric) (Kumar, Barua, Sulakhiya, & Sharma, 2017; Sahin et al., 2014; Topcu-Tarladacalisir, Sapmaz-Metin, & Karaca, 2016; Ueki, Ueno, Morishita, & Maekawa, 2013; Waseem & Parvez, 2013), grape seed proanthocyanidin extract (Hassan, Edrees, El-Gamel, & El-Sayed, 2014; Saad, Youssef, & El-Shennawy, 2009), honey (Hamad et al., 2015; Huang et al., 2017; Ibrahim, Eldaim, & Abdel-Daim, 2016), and pomegranate (flower, rind and seed) extract (Bakir et al., 2015; Boroushaki et al., 2015; Karwasra et al., 2016; Motamedi et al., 2014) have the potential to attenuate the nephrotoxic side effects of cisplatin through reduction of oxidative stress, mitochondrial apoptosis and inflammation responses. Among these natural products, the renal protective effect of grape seed proanthocyanidin has also been linked to inhibition of ER stress-induced apoptosis (caspase 12 activation) (Gao et al., 2014). In addition, curcumin is able to prevent cisplatin-induced renal alterations in transporter expression in mitochondrial bioenergetics, ultrastructure and dynamic (Ortega-Dominguez et al., 2017). Curcumin has also been reported to exert protection when used as a pre-treatment or co-treatment with cisplatin therapy, but not as a post-treatment (Kumar et al. ,2017). Amelioration of cisplatin-induced nephrotoxicity by pomegranate flower extract is gender-related, although reasons for this are not clear (Jilanchi et al., 2014; Motamedi et al., 2014).

Several food-derived antioxidants are known to have bifunctionality, since they not only scavenge ROS, but also increase GSH content, as well as enhance the expression and activities of antioxidant enzymes (catalase, GPx, GR, GST, HO-1, NQO1, SOD, and TrxR) through Nrf2. Among these dietary antioxidants, capsaicin, ellagic acid, epigallocatechin-3-O-gallate, α-lipoic acid, lycopene, quercetin, resveratrol, sulforaphane, tannins, and vitamin B2, C, and E, have been reported to not only ameliorate cisplatin-induced renal damage through their antioxidant and anti-inflammatory effects, but also potentiate the antineoplastic effects of cisplatin by mechanisms such as downregulation of drug efflux transporters, and upregulation of p53 protein in cancer cells, as well as reduction of cancer stem cell population, generally accepted to be important for drug resistance and rumor relapse (Dasari & Tchounwou, 2014; Miller et al., 2010; Volarevic et al., 2019).

Based on all these preclinical studies, dietary intervention with antioxidants from natural products or food seems to be a favorable approach to prevent cisplatin-induced kidney damage without compromising its antitumor activities (Kumar et al., 2017; Patricia Moreno-Londono et al., 2017; Volarevic et al., 2019; Wang et al., 2014). However, current animal models used in cisplatin-induced renal damage research have several limitations, e.g., the use of animals that do not present cancer or are young, as well as models that induce acute not chronic kidney disease, which has greater clinical relevance (Volarevic et al., 2019). Some effects have been made to demonstrate the beneficial effect of antioxidants as an adjuvant therapy in humans but to date, these have not been comprehensive. Daily honey consumption by cancer patients has been shown to significantly reduce BUN and Cr levels during cisplatin treatment (Osama et al., 2017). Lycopene has been reported to improve renal functions (GFR) in cancer patients under cisplatin therapy (Mahmoodnia, Mohammadi, & Masumi, 2017). In addition, in patients with reduced: oxidized vitamin C ratios >7.5, vitamin supplementation (vitamin C, vitamin E and selenium) attenuated cisplatin-induced loss of renal function (Weijl et al., 2004). At this stage, more clinical approaches are still needed to support these types of “natural antioxidant” interventions as a way of reducing cisplatin toxicities.

6. Conclusion and future direction

Cisplatin combines an unusual clinical pharmacology, with bifunctional alkylating functions sharing heavy metal characteristics. With the halogens acting as leaving groups, electrophilic intermediates are free to interact with an extensive range of cellular nucleophiles. Given that there is more than 40 years of clinical experience dealing with the side effects of cisplatin, there is a certain degree of familiarity with how patients under treatment should be managed. Unusually, detoxification of the drug with GSH systems contributes to kidney toxicity and the obvious importance of redox pathways in its metabolism do provide a fascinating background to view pharmacology of other metal containing alkylating agents, including analogues.

Abbreviation

AOAA

aminooxyacetic acid

APN

aminopeptidase N

BUN

blood urea nitrogen

CCBL

cysteine-S-conjugate beta-lyase

Cr

creatinine

Ctr1

copper transporter 1

CYP

cytochrome P450

ER

endoplasmic reticulum

ETC

electron transport chain

GFR

glomerular filtration rate

GGT

gamma glutamyl transpeptidase

GPx

glutathione peroxidase

GR

glutathione reductase

Grx

glutaredoxin

GSH

glutathione

GSSG

glutathione disulfide

GST

glutathione S-transferase

MATE1

multidrug and toxin extrusion transporter 1

mitAAT

mitochondrial aspartate aminotransferase

NOX

NADPH oxidase

OCT2

organic cation transporter 2

PLP

pyridoxal 5′-phosphate

Prx

peroxiredoxin

ROS

reactive oxygen species

SOD

superoxide dismutase

Trx

thioredoxin

TrxR

thioredoxin reductase

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