Protective effect of gallic acid and gallic acid-loaded Eudragit-RS 100 nanoparticles on cisplatin-induced mitochondrial dysfunction and inflammation in rat kidney

Cisplatin is used as a chemotherapy drug in the treatment of various types of cancer. Mitochondrial dysfunction, oxidative stress and inflammation have been identified as major mechanisms of cisplatin nephrotoxicity. The present study investigated the protective effects of pure gallic acid and nanoparticle gallic acid nanoparticles (nano-gallic acid) on cisplatin induced nephrotoxicity. Nano-gallic acid was prepared by double emulsions-solvent evaporation technique using Eudragit RS 100 polymer and polyvinyl alcohol as carrier. Then, the physicochemical characterization of the nanoparticles was examined. In the present study, renal mitochondria were isolated using different centrifugal methods. Our data indicated that the doses of 50 and 100 mg/kg gallic acid and 10 mg/kg nano-gallic acid significantly decreased mitochondrial reactive oxygen species (ROS) formation, mitochondrial membrane damage (ΔΨm), mitochondrial malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and significantly increased mitochondrial glutathione (GSH), mitochondrial superoxide dismutase (MnSOD), mitochondrial glutathione peroxidase (GPX) and mitochondrial catalase compared to the cisplatin treated group. Histopathological studies also confirmed biochemical tests. Finally, our results confirmed that the pure gallic acid and its nanoparticle improved renal oxidative stress, inflammation and mitochondrial dysfunction in acute nephrotoxicity induced by cisplatin in rat. Nano-gallic acid (10 mg/kg) was selected as the most effective dose. The findings of this study showed the superiority of nano-gallic acid against pure gallic acid. In conclusion, nano-gallic acid-loaded Eudragit-RS 100 as a novel antioxidant can be considered in the treatment of renal complications of cisplatin.     

The dietary isoflavone daidzein mitigates oxidative stress,apoptosis, and inflammation in CDDP‐induced kidney injury in rats: Impact of the MAPK signaling pathway

Cisplatin‐induced nephrotoxicity persists as a clinical problem despite several supportive measures to alleviate renal damage. Daidzein (DZ), a dietary isoflavone having antioxidant and anti‐inflammatory activity, is investigated in this study for protective effects against cisplatin‐induced renal injury in rats. DZ (25, 50, or 100 mg/kg; intraperitoneally; 10 days) was administered along with Cisplatin, single dose, on the 7th day of the experiment. On the 11th day, the rats were euthanized, and different samples were collected for analysis. Biochemical, histopathological, and molecular parameters were assessed to evaluate the effect of daidzein. Cisplatin injection resulted in renal dysfunction, lipid peroxidation that led to consumption of antioxidants, exaggerated apoptosis, and inflammation. These changes were associated with increase in the signaling proteins. DZ attenuated the toxic effects of cisplatin on the kidney at 100 mg/kg dose. The study concludes with the finding that daidzein imparts protection against the nephrotoxic effect of Cisplatin and can be considered as a novel, potential therapy.     

Effects of cisplatin on mitochondrial function and autophagy-related proteins in skeletal muscle of rats

Cisplatin is widely known as an anti-cancer drug. However, the effects of cisplatin on mitochondrial function and autophagy-related proteins levels in the skeletal muscle are unclear. The purpose of this study was to investigate the effect of different doses of cisplatin on mitochondrial function and autophagy-re-lated protein levels in the skeletal muscle of rats. Eight-week-old male Wistar rats (n = 24) were assigned to one of three groups; the first group was administered a saline placebo (CON, n = 10), and the second and third groups were given 0.1 mg/kg body weight (BW) (n = 6), and 0.5 mg/kg BW (n = 8) of cisplatin, respectively. The group that had been administered 0.5 mg cisplatin exhibited a reduced BW, skeletal muscle tissue weight, and mitochondrial function and upregulated levels of autophagy-related proteins, including LC3II, Beclin 1, and BNIP3. Moreover, this group had a high LC3 II/I ratio in the skeletal muscle; i.e., the administration of a high dose of cisplatin decreased the muscle mass and mitochondrial function and increased the levels of autophagy-related proteins. These results, thus, suggest that reducing mitochondrial dysfunction and autophagy pathways may be important for preventing skeletal muscle atrophy following cisplatin administration.     

Dimethylthiourea protects against mitochondrial oxidative damage induced by cisplatin in liver of rats

Cisplatin is one of the most effective chemotherapeutic agents. However, at higher doses liver injury may occur. The purpose of this study was to explore whether the hydroxyl radical scavenger dimethylthiourea (DMTU) protects against cisplatin-induced oxidative damage in vivo and to define the mitochondrial pathways involved in cytoprotection. Adult male Wistar rats (200–220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml/100 g body weight). The DMTU group was given only DMTU (500 mg/kg body weight, i.p), followed by 125 mg/kg body weight, i.p. (twice a day) until sacrifice. The cisplatin group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The DMTU + cisplatin group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until sacrifice (72 h after the treatment). DMTU did not present any direct effect on mitochondria and substantially inhibited cisplatin-induced mitochondrial damage in liver, therefore preventing elevation of AST and ALT serum levels. DMTU protected against (a) decreased hepatic ATP levels; (b) lipid peroxidation; (c) cardiolipin oxidation; (d) sulfhydryl protein oxidation; (e) mitochondrial membrane rigidification; (f) GSH oxidation; (g) NADPH oxidation; (h) apoptosis. Results suggest that antioxidants, particularly hydroxyl radical scavengers, protect liver mitochondria against cisplatin-induced oxidative damage. Several mitochondrial changes were delineated and proposed as interesting targets for cytoprotective strategy.     

Amelioration of cisplatin-induced nephrotoxicity by grape seed extract and fish oil is mediated by lowering oxidative stress and DNA damage

Cisplatin (CP) is a chemotherapeutic drug used in treatment of malignancies. However, its clinical utility is limited by nephrotoxicity. The purpose of the present study was to investigate the protective role of grape seed proanthocyanidin extract (GSPE) (100 mg/kg/day) or fish oil (FO) (5 ml/kg/day) against cisplatin induced nephrotoxicity in terms of biochemical parameters, oxidative stress and DNA damage. CP nephrotoxiciy is manifested by increased levels of serum creatinine, urea and uric acid, accompanied by their decrease in urine. Na, K and Ca levels were altered in both serum and urine. In addition, cisplatin caused a decrease in renal GSH, SH-group, SOD, GST, and Na–K–ATPase levels. However the levels of MDA, H₂O₂ and NO were increased. Also, we assessed the renal genotoxic potential of cisplatin as manifested by an increase in the tail length of DNA, tail intensity (DNA %) and tail moment. On the other hand, administration of GSPE or FO pre-cisplatin treatment ameliorated the current changes in most of the above tested parameters, particularly oxidative stress, endogenous antioxidant defense system and DNA damage indicating their curative effect. Thus, it can be concluded that the consumption of GSPE or FO might be useful for preventing nephrotoxicity caused by cisplatin treatment.     

Chemopreventive effect of bilberry (Vaccinium myrtillus) against cisplatin-induced oxidative stress and DNA damage as shown by the comet assay in peripheral blood of rats

The aim of this study was to evaluate the chemopreventive effect of bilberry on cisplatin induced oxidative stress and DNA damage in rat blood. Twenty-one female Wistar-Albino rats were divided into three groups: group I — untreated; group II — treated with cisplatin (single dose 7.5 mg/kg b.w.); and group III — treated with cisplatin (single dose 7.5 mg/kg b.w.) and bilberry (200 mg/kg b.w. for 10 days). Antioxidant enzyme systems including superoxide dismutase, catalase, glutathione peroxidase and the level of malondialdehyde (MDA) that might occur on erythrocytes have been determined and single cell gel electrophoresis (comet) was utilized to evaluate the DNA damage in lymphocytes. Treatment with cisplatin has increased the levels of MDA and decreased antioxidant enzymes in erythrocytes. Comet assay showed significantly higher values at dose of 7.5 mg/kg cisplatin as the result of oxidative DNA damage when compared to the control group. Cisplatin treatment with bilberry resulted in a highly significant (P < 0.05) decreased in the lymphocytes DNA when compared to the cisplatin group. Bilberry has been effective on antioxidant enzyme systems and MDA level and significantly decreased the comets. Our results indicate that bilberry is capable of preventing genotoxic and cytotoxic damage caused by cisplatin in peripheral blood cells in rats.     

Nephroprotective effect of bee honey and royal jelly against subchronic cisplatin toxicity in rats

Cisplatin is one of the most potent and effective chemotherapeutic agents. However, its antineoplastic use is limited due to its cumulative nephrotoxic side effects. Therefore, the present study was undertaken to examine the nephroprotective potential of dietary bee honey and royal jelly against subchronic cisplatin toxicity in rats. Male Wistar rats were randomly divided into controls, cisplatin-treated, bee honey-pretreated cisplatin-treated and royal jelly-pretreated cisplatin-treated groups. Bee honey and royal jelly were given orally at doses of 20 and 100 mg/kg, respectively. Subchronic toxicity was induced by cisplatin (1 mg/kg bw, ip), twice weekly for 10 weeks. Cisplatin treated animals revealed a significant increase in serum level of renal injury products (urea, creatinine and uric acid). Histopathologically, cisplatin produced pronounced tubulointerstitial injuries, upregulated the fibrogenic factors, α-smooth muscle actin (α-SMA) and transforming growth factor β1(TGF-β1), and downregulated the cell proliferation marker, bromodeoxyuridine (Brdu). Dietary bee honey and royal jelly normalized the elevated serum renal injury product biomarkers, improved the histopathologic changes, reduced the expression of α-SMA and TGF-β1 and increased the expression of Brdu. Therefore, it could be concluded that bee honey, and royal jelly could be used as dietary preventive natural products against subchronic cisplatin-induced renal injury.     

Effect of pre-treatment with St John's Wort on nephrotoxicity of cisplatin in rats

An herbal health care supplement, St John's Wort (SJW, Hypericum perforatum) has become widely used in the treatment of depression, and is known to interact with therapeutic drugs. Here we report a preventive effect of SJW on cisplatin nephrotoxicity in rats. Rats were given SJW (400 mg/kg/day, p.o.) for 10 consecutive days, and were injected with cisplatin (5 mg/kg, i.v.) on the day after the final SJW treatment. Cisplatin treatment increased the serum creatinine level, which is an index of nephrotoxicity, to 1.51+/-0.22 mg/dl (mean+/-SE) from 0.28+/-0.05 mg/dl (control) on day 5 after the cisplatin injection. This increase fell significantly to 0.86+/-0.13 mg/dl by pre-treatment with SJW. Cisplatin-induced histological abnormality of the kidney was blocked by pre-treatment with SJW. When SJW was administered for 10 days, the amounts of renal metallothionein (MT) and hepatic multidrug resistance protein 2 (Mrp2) were increased to 164.8+/-13.0% and 220.8+/-39.3% (mean+/-SE) of controls, respectively. GSH levels in the kidney and liver were not changed. Total and free cisplatin concentration in serum was not influenced by SJW treatment. In conclusion, the results suggest that pre-treatment with SJW may diminish cisplatin nephrotoxicity.     

Cisplatin induced nephrotoxicity and the modulating effect of glutathione ester

The objective of this study was to assess the therapeutic advantage of glutathione ester along with cisplatin. Comparisons were made with renal reduced glutathione, enzymatic antioxidants, and lipid peroxidation levels. Cisplatin caused differential toxic effects on renal antioxidants and lipid peroxidation. However administration of glutathione ester modulates the toxic effects of cisplatin observed in renal antioxidants and lipid peroxidation. The finding that glutathione ester co-administration along with cisplatin is more effective and advantageous in protecting against the nephrotoxicity of cisplatin when it was given alone.     

Protection against cisplatin-induced nephrotoxicity by Cu(II)2(3,5-diisopropylsalicylate)4

The ability of Cu(II)(2)(3,5-diisopropylsalicylate)(4), CuDIPS, which exhibits superoxide dismutase (SOD)-like activity, to prevent cisplatin-induced nephrotoxicity was examined in rats. Rats were divided into four groups and treated as follows: (i) vehicle control; (ii) cisplatin (16 mg/kg, intraperitoneally); (iii) CuDIPS (10 mg/kg, intraperitoneally); and (iv) cisplatin plus CuDIPS. Rats were sacrificed 3 days post-treatment. Cisplatin alone resulted in significantly increased plasma creatinine and urea. Administration of 10 mg/kg CuDIPS prevented the cisplatin-induced elevation of plasma creatinine and urea and protected against kidney damage. Relative to controls, rats that received cisplatin treatment displayed a decrease of reduced glutathione (GSH) and elevated platinum and thiobarbituric acid reactive substances (TBARS) levels in the kidney. In comparison with controls, activities of antioxidant enzymes (SOD, CAT, GSH-Px and GSH-Rd) were also reduced in the kidney of rats treated with cisplatin. Administration of 10 mg/kg CuDIPS prevented cisplatin-induced alterations in renal platinum, GSH, TBARS, and antioxidant enzyme activities. This study suggests that the protection offered by CuDIPS against cisplatin-induced nephrotoxicity is partly related to maintenance of renal antioxidant systems.     

Effects of organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione on cisplatin induced nephrotoxicity and genotoxicity: an investigation of the influence of the compound on oxidative stress and antioxidant enzyme system

Cisplatin is one of the most active cytotoxic agents used in the treatment of cancer. However, cisplatin therapy is also associated with severe side effects like nephrotoxicity and genotoxicity. Free oxygen radicals are known to play a major role in cisplatin induced toxicities. Selenium is believed to be an important trace element and dietary antioxidant because of its ability to scavenge free oxygen radicals, thereby preventing cells from oxidative stress. The purpose of this study is to evaluate the protective role of a novel naphthalimide based organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione against cisplatin induced toxicities in Swiss albino mice. Cisplatin was administered intraperitoneally (5 mg/kg b.w.) and the organoselenium compound was given by oral gavages (3 mg/kg b.w.) in concomitant and pretreatment schedule. The results showed that the test compound substantially reduced cisplatin induced reactive oxygen species generation and lipid peroxidation in kidney as well as blood urea nitrogen and creatinine levels in serum. Treatment with organoselenium compound was also able to restore the renal antioxidant system by modulating the cisplatin induced depleted activities of glutathione S-transferase, thioredoxin reductase, superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione level. In addition, the organoselenium compound could efficiently minimize cisplatin induced chromosomal aberrations in bone marrow cells and extent of DNA damage in lymphocytes. Furthermore, the chemoprotective efficacy of the compound against cisplatin induced toxicity was confirmed by histopathological evaluation. The results suggest that the organoselenium compound has the potential to protect against cisplatin induced nephrotoxicity and genotoxicity in part by scavenging reactive oxygen species and by up regulating the antioxidant enzyme system.     

Benfotiamine Enhances Antioxidant Defenses and Protects against Cisplatin‐Induced DNA Damage in Nephrotoxic Rats

The objective of the present study was to assess superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), paraoxonase (PON1), glutathione reductase (GR), and catalase (CAT) activities ratio and their relationship with DNA oxidative damage in rats treated with cisplatin (3 mg/kg bwt/day) in the presence and absence of benfotiamine (100 mg/kg/day) for 25 days. Cisplatin‐induced renal damage was evidenced by renal dysfunction and elevated oxidative stress markers. SOD activity and levels of nitric oxide, protein carbonyl, malondialdehyde, and 8‐hydroxy‐2'‐deoxyguanosine were significantly increased by cisplatin treatment. Moreover, the ratios of GPx/GR, SOD/GPx, SOD/CAT, and SOD/PON1 were significantly increased compared to control. In contrast, glutathione levels were significantly decreased by cisplatin treatment. Simultaneous treatment of rats with cisplatin and benfotiamine ameliorate these variables to values near to those of control rats. This study suggests that benfotiamine can prevent cisplatin‐induced nephrotoxicity by inhibiting formation reactive species of oxygen and nitrogen. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:398‐405, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21501     

Morin Hydrate Mitigates Cisplatin‐Induced Renal and Hepatic Injury by Impeding Oxidative/Nitrosative Stress and Inflammation in Mice

Cisplatin is a widely used chemotherapeutic drug; however, it induces damage on kidney and liver at clinically effective higher doses. Morin hydrate possesses antioxidant, anti‐inflammatory, and anticancer properties. Therefore, we aimed to investigate the effects of morin hydrate (50 and 100 mg/kg, orally) against the renohepatic toxicity induced by a high dose of cisplatin (20 mg/kg, intraperitoneally). Renal and hepatic function, oxidative/nitrosative stress, and inflammatory markers along with histopathology were evaluated. Morin hydrate ameliorated cisplatin‐induced renohepatic toxicity significantly at 100 mg/kg as evidenced from the significant reversal of cisplatin‐induced body weight loss, mortality, functional and structural alterations of kidney, and liver. The protective role offered by morin hydrate against cisplatin‐induced renohepatic toxicity is by virtue of its free radical scavenging property, thereby abating the depletion of cellular antioxidant defense components and through modulation of inflammatory cytokines. We speculate morin hydrate as a protective candidate against renohepatic toxicity of cisplatin.     

Protective effect of bilberry (Vaccinium myrtillus L.) on cisplatin induced ovarian damage in rat

Cisplatin is one of the most effective chemotherapeutic agents but injury may occur at higher doses. The aim of this study was to investigate the effect of bilberry on cisplatin induced toxic effects in rat ovary. Twenty-one female Wistar–Albino rats were utilized to form three groups: In group 1 (control group), each rat received intraperitoneal injection of 1 mL of 0.9 % NaCl saline solution during 10-days. In group 2 (cisplatin group), a single dose of 7.5 mg/kg b.w. cisplatin was given. In group 3 (cisplatin + bilberry group), a single dose of 7.5 mg/kg cisplatin and bilberry at 200 mg/kg b.w. were given for 10 days. Ovaries were surgically removed in all groups and prepared for biochemical and light microscopic investigations at the examination times. Malondialdehyde (MDA) levels and activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) of tissue samples were measured. Histopathological damages in cisplatin administrated rats were seen such as severe edema, vascular congestion, hemorrhage and follicular degeneration in the ovary tissue. Moderate pathological alterations were observed in rats treated with bilberry plus cisplatin. Cisplatin administration significantly increased MDA production and decreased SOD, CAT, GPx and GST activities in the ovarian tissue when compared to the control group (p < 0.05). Cisplatin + bilberry administration increased antioxidant enzymes activities and reduced MDA levels. Bilberry administration seems to reduce the cisplatin induced ovarian toxicity thus it alleviates free radical damage. But it dose not protect completely rat ovary tissues.     

Renal protective effects of arjunolic acid in a cisplatin-induced nephrotoxicity model

Cisplatin is the first platinum-containing anti-cancer drugs. Cisplatin notable side effect of nephrotoxicity limits its use in clinic. Meanwhile, arjunolic acid possesses anti-inflammatory properties and plays protective roles against chemically induced organ pathophysiology. This study was conducted to find out whether arjunolic acid could attenuate kidney damage in rats, and to elucidate its possible mechanism of action. Fifty rats were treated with cisplatin (10 mg/kg) in the presence/absence of 100 or 250 mg/kg arjunolic acid. Arjunolic acid is given 1 h after cisplatin. Morphological changes were assessed in kidney sections stained with Hematoxylin/Eosin and Masson Trichrome. Kidney samples were used for measurements of transforming growth factor (TGF)-β1 and its type 1 receptor (TGF-βR1), tumor necrosis factor (TNF)-α and interleukin (IL)-1β by ELISA. Gene expression NFκB was determined by real time-PCR. Kidney tissue apoptosis was assessed by measuring the activities of caspase-3/8/9. The renal protective effect of arjunolic acid was confirmed by approximately normal appearance of renal tissue and the relatively unaffected serum creatinine and urea levels. Furthermore, arjunolic acid showed dose dependent reduction in cisplatin-induced elevation in renal levels of TGF-βR1, TGF-β1, TNF-α, IL-1β and caspases. These findings demonstrated that arjunolic acid attenuates cisplatin nephrotoxicity either indirectly by enhancing body antioxidant activity or directly through several mechanisms, including inhibition of pro-inflammatory cytokines, blocking activation of TGF-β1, and anti-apoptotic effects.     

Distribution and excretion of a phosphorothioate oligonucleotide in rats with experimentally induced renal injury

The effects of renal injury on the urinary excretion and tissue distribution of a 20-mer phosphorothioate oligonucleotide were investigated in male Sprague-Dawley rats. Renal injury was produced by treating the rats with either 5.0 mg/kg cisplatin or 2.5 mg/kg of a monoclonal antibody (mAb) directed toward Thy1.1. Controls received saline. Three days after cisplatin treatment or 2 days after anti- Thy1.1 treatment, the rats received 10 mg/kg ISIS 3521. Blood was collected at various times to assess the plasma concentrations of ISIS 3521, and rats were killed at various times from 6 to 48 hours after intravenous (i.v.) infusion of oligonucleotide to assess tissue concentrations by capillary gel electrophoresis (CGE). Cisplatin and anti-Thy1.1 antibody produced histologic and biochemical changes consistent with proximal tubular damage and glomerular damage, respectively. Urinary excretion of oligonucleotides was increased 2- to 4-fold of control; however, this amount accounted for only 1% to 2% of dose compared to 0.5% in controls. Proximal tubular damage reduced renal accumulations of ISIS 3521 and other oligonucleotide metabolites, but there were no obvious compensatory increases in concentrations in other organs except for a slight increase in spleen levels of total oligonucleotide. Glomerular damage was not associated with any change in oligonucleotide disposition. Immunohistochemical studies showed no evidence of alterations in the pattern of distribution within the injured kidney. The data suggest that acute renal dysfunction, either renal tubular or glomerular, does not markedly alter the urinary elimination and tissue deposition of a phosphorothioate oligonucleotide.     

Role of the DNA Base Excision Repair Protein,APE1 in Cisplatin,Oxaliplatin, or Carboplatin Induced Sensory Neuropathy

Although chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of platinum drugs, the mechanisms of this toxicity remain unknown. Previous work in our laboratory suggests that cisplatin-induced CIPN is secondary to DNA damage which is susceptible to base excision repair (BER). To further examine this hypothesis, we studied the effects of cisplatin, oxaliplatin, and carboplatin on cell survival, DNA damage, ROS production, and functional endpoints in rat sensory neurons in culture in the absence or presence of reduced expression of the BER protein AP endonuclease/redox factor-1 (APE1). Using an in situ model of peptidergic sensory neuron function, we examined the effects of the platinum drugs on hind limb capsaicin-evoked vasodilatation. Exposing sensory neurons in culture to the three platinum drugs caused a concentration-dependent increase in apoptosis and cell death, although the concentrations of carboplatin were 10 fold higher than cisplatin. As previously observed with cisplatin, oxaliplatin and carboplatin also increased DNA damage as indicated by an increase in phospho-H2AX and reduced the capsaicin-evoked release of CGRP from neuronal cultures. Both cisplatin and oxaliplatin increased the production of ROS as well as 8-oxoguanine DNA adduct levels, whereas carboplatin did not. Reducing levels of APE1 in neuronal cultures augmented the cisplatin and oxaliplatin induced toxicity, but did not alter the effects of carboplatin. Using an in vivo model, systemic injection of cisplatin (3 mg/kg), oxaliplatin (3 mg/kg), or carboplatin (30 mg/kg) once a week for three weeks caused a decrease in capsaicin-evoked vasodilatation, which was delayed in onset. The effects of cisplatin on capsaicin-evoked vasodilatation were attenuated by chronic administration of E3330, a redox inhibitor of APE1 that serendipitously enhances APE1 DNA repair activity in sensory neurons. These outcomes support the importance of the BER pathway, and particularly APE1, in sensory neuropathy caused by cisplatin and oxaliplatin, but not carboplatin and suggest that augmenting DNA repair could be a therapeutic target for CIPN.     

Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy

Cisplatin is a widely used antineoplastic agent; however, its major limitation is the development of dose-dependent nephrotoxicity whose precise mechanisms are poorly understood. Here we show not only that mitochondrial dysfunction is a feature of cisplatin nephrotoxicity, but also that targeted delivery of superoxide dismutase mimetics to mitochondria largely prevents the renal effects of cisplatin. Cisplatin induced renal oxidative stress, deterioration of mitochondrial structure and function, an intense inflammatory response, histopathological injury, and renal dysfunction. A single systemic dose of mitochondrially targeted antioxidants, MitoQ or Mito-CP, dose-dependently prevented cisplatin-induced renal dysfunction. Mito-CP also prevented mitochondrial injury and dysfunction, renal inflammation, and tubular injury and apoptosis. Despite being broadly renoprotective against cisplatin, Mito-CP did not diminish cisplatin's antineoplastic effect in a human bladder cancer cell line. Our results highlight the central role of mitochondrially generated oxidants in the pathogenesis of cisplatin nephrotoxicity. Because similar compounds seem to be safe in humans, mitochondrially targeted antioxidants may represent a novel therapeutic approach against cisplatin nephrotoxicity.     

Adverse effects of anti-tumor drug, cisplatin, on rat kidney mitochondria: disturbances in glutathione peroxidase activity

This study was designed to clarify mechanisms responsible for cisplatin-induced nephrotoxicity together with the effect of selenium. Rats were divided into 3 groups: the cisplatin group; cisplatin (60 mg/kg) was administered intraperitoneally once, the cisplatin + Se group; cisplatin (60 mg/kg) once, and selenious acid (10 mumol/kg) were administered intraperitoneally once a day for 5 consecutive days, the control group; untreated. In each group, mitochondrial respiratory function, enzymic activities in mitochondrial respiratory chain and glutathione peroxidase, and plasma creatinine and BUN contents were measured. In the cisplatin group, decreases in mitochondrial respiratory function, enzymic activities in the respiratory chain and glutathione peroxidase, and increases in plasma creatinine and BUN contents were observed compared with the control group, while the cisplatin + Se group lessened these impairments. These results suggested that cisplatin-induced nephrotoxicity was closely related to mitochondrial dysfunction through the impairment of glutathione peroxidase. This toxicity might be ascribed to free radical mediated-injury. We propose here that, with selenium, higher dose administration of cisplatin to patients might be applicable.     

Diacerein ameliorates kidney injury induced by cisplatin in rats by activation of Nrf2/Ho-1 pathway and Bax down-regulation

Cisplatin is an antineoplastic medicine used for solid tumor treatment. The main side effect that limits its dose is nephrotoxicity. Diacerein has been used for the treatment of joint diseases like osteoarthritis. It also has exhibited analgesic effects and antipyretic activities in animal models so this study targets to indicate the diacerein effect on nephrotoxicity induced by cisplatin in rats. Rats were distributed into four groups: normal healthy control; diacerein, which received diacerein daily by gastric gavage (50 mg/kg/day); cisplatin, which received only one intraperitoneal injection of cisplatin (6 mg/kg) and cisplatin and diacerein, which received diacerein daily after the cisplatin injection till 7th and 12th days, respectively. Diacerein treatment decreased kidney function markers so the cisplatin effect was reversed. Also, diacerein increased the renal antioxidants and decreased oxidative stress. Diacerein up-regulated Ho-1 (heme oxygenase 1), Nrf2 (Nuclear factor erythroid 2–related factor 2) and endothelial nitric oxide synthase (eNOS) genes expression, while down-regulated Bcl-2-associated X protein (Bax) gene expression. Furthermore, the renal transforming growth factor beta-1 (TGF-β1) decreased by the diacerein effect. Consequently, diacerein has a curative effect against cisplatin due to its anti-inflammatory, antioxidant, and antiapoptotic properties.