Carvedilol protects against cisplatin-induced oxidative stress, redox state unbalance and apoptosis in rat kidney mitochondria

Cisplatin is a highly effective chemotherapeutic agent which causes severe nephrotoxicity. Studies have suggested that reactive oxygen species, mainly generated in mitochondria, play a central role in cisplatin-induced renal damage. A wide range of antioxidants have been evaluated as possible protective agents against cisplatin-induced nephrotoxicity; however a safe and efficacious compound has not yet been found. The present study is the first to evaluate the protective potential of carvedilol, a beta-blocker with strong antioxidant properties, against the mitochondrial oxidative stress and apoptosis in kidney of rats treated with cisplatin. The following cisplatin-induced toxic effects were prevented by carvedilol: increased plasmatic levels of creatinine and blood urea nitrogen (BUN); lipid peroxidation, oxidation of cardiolipin; oxidation of protein sulfhydryls; depletion of the non-enzymatic antioxidant defense and increased activity of caspase-3. Carvedilol per se did not present any effect on renal mitochondria. It was concluded that carvedilol prevents mitochondrial dysfunction and renal cell death through the protection against the oxidative stress and redox state unbalance induced by cisplatin. The association of carvedilol to cisplatin chemotherapy was suggested as a possible strategy to minimize the nephrotoxicity induced by this antitumor agent.     

Cisplatin-induced genotoxic effects and endogenous glutathione levels in mice bearing ascites Dalton's lymphoma

cis-Diaminedichloroplatinum(II), commonly known as cisplatin, treatment of mice for 24-96, 30 h and 10 days caused the development of chromosomal aberrations in bone marrow cells as well as in Dalton's lymphoma (DL) cells, micronuclei (MN) in bone marrow cells and abnormalities in sperm heads, and it indicates the genotoxic potential of cisplatin in the host. Cisplatin exerts differential effects on the chromosomes of the bone marrow and tumor cells. Combination treatment of cisplatin with L-buthionine(S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, enhanced these cisplatin-induced genotoxic effects, but supplementing glutathione level with cysteine, its precursor, reduced the cisplatin-induced genotoxicity. The reduction in cellular glutathione level may facilitate increased intracellular accumulation and binding of drug to DNA to enhance the frequency of genotoxicity parameters. These findings support the possible involvement of glutathione as an important intracellular protective agent and suggest that differences in its levels may be one of the factors in the varying sensitivity of cells to cisplatin-induced genotoxic effects in the mice bearing ascites Dalton's lymphoma.     

Epicatechin protects auditory cells against cisplatin-induced death

Cisplatin, a chemotherapeutic drug that is widely used to treat various cancers, promotes ototoxicity at higher doses. In this study, the effect of epicatechin (EC) on cisplatin-induced hair cell death was investigated in a cochlear organ of Corti-derived cell line, HEI-OC1, and in vivo in zebrafish. Cisplatin promoted apoptosis and altered mitochondrial membrane potential (MMP) in HEI-OC1 cells. EC inhibited cisplatin-induced apoptosis and intracellular reactive oxygen species (ROS) generation. Labeling of zebrafish lateral line hair cells by the fluorescent dye YO-PRO1 was lost upon exposure to cisplatin, and EC protected against this cisplatin-induced loss of labeling in a dose-dependent manner. Scanning and transmission electron micrographs showed that treatment with EC protected against cisplatin-induced loss of kinocilium and stereocilia in zebrafish neuromasts. These results suggest that EC prevents cisplatin-induced ototoxicity by blocking ROS generation and by preventing changes in MMP.     

Chemoprotective action of resveratrol and genistein from apoptosis induced in human peripheral blood lymphocytes

Extensive research is being carried out to analyse the importance of plant products such as resveratrol and genistein, which are known to exert a variety of pharmacological effects. This study aims at evaluating the protective role of these compounds against the apoptosis induced in normal cells by cytotoxic anticancer agents such as cisplatin and mytomycin C during therapy. Despite the broad antineoplastic action of cisplatin and mitomycin C, their genotoxicity in normal cell might lead to the induction of secondary malignancies. Therefore, the problem of identifying plant compounds, which might exert protective action in normal cells, gains lot of significance. We have analyzed the chemoprotective effect of plant compounds on peripheral blood human lymphocytes when exposed to cisplatin and mitomycin C by pre-treating and post-treating them with resveratrol and genistein at 100 microM concentration Biochemical alterations occurring in many cells during apoptosis include loss of plasma membrane phospholipid asymmetry, DNA fragmentation, and activation of caspase-3, et cetera, and have been assessed. Fluorescence microscopy, flow cytometric techniques have clearly demonstrated that resveratrol and genistein are efficient in protecting lymphocytes undergoing DNA damage when exposed to cisplatin and mitomycin C and exerted their activity by reducing the caspase 3 expression. An interesting observation is that, these compounds offered their protective effect by reducing their apoptotic potential on membrane and nucleic acids against cytotoxic agents, cisplatin, and mitomycin C. These results suggest that resveratrol and genistein might be useful for risk assessments in advance of clinical trials and could be considered as a strong candidate in pharmacogenomics or nutriprotective arena.     

Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity

We reported earlier that reactive oxygen species are implicated in necrotic injury induced by a transient exposure of cultured renal tubular cells to a high concentration of cisplatin but not in apoptosis occurring after continuous exposure to a low concentration of cisplatin. We report here the protective effect of cyclic AMP against cisplatin-induced necrosis in cultured renal tubular cells as well as cisplatin-induced acute renal failure in rats. Several pharmacological agents that stimulate cyclic AMP signaling, including the nonhydrolyzable cyclic AMP analogue dibutyryl cyclic AMP, forskolin, 3-isobutyl-1-methylxanthine, and a prostacyclin analogue, beraprost, prevented cisplatin-induced cell injury in a protein kinase A-dependent manner. Cisplatin enhanced lipid peroxidation, decreased CuZn superoxide dismutase (SOD) while enhancing MnSOD activity, and increased cellular tumor necrosis factor-alpha (TNF-alpha) content. The elevation of TNF-alpha content and cell injury induced by cisplatin were attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors including SB203580 and PD169316. Indeed, cisplatin increased the number of phosphorylated p38 MAPK-like immunoreactive cells. These intracellular events were all reversed by antioxidants such as N-acetylcysteine (NAC) and glutathione or cyclic AMP analogues. The in vivo acute renal injury after cisplatin injection was associated with the elevation of renal TNF-alpha content. The cisplatin-induced renal injury and the increase in TNF-alpha content were reversed by NAC or beraprost. These findings suggest that cyclic AMP protects renal tubular cells against cisplatin-induced oxidative injury by obliterating reactive oxygen species and subsequent inhibition of TNF-alpha synthesis through blockade of p38 MAPK activation.     

Cisplatin-induced cell death in Saccharomyces cerevisiae is programmed and rescued by proteasome inhibition

Cisplatin is a highly effective chemotherapeutic drug used in the treatment of several tumors. It is a DNA-damaging agent that induces apoptosis of rapidly proliferating cells, an important factor underlying its therapeutic efficacy. Unfortunately, cellular resistance occurs often. A large fraction of tumor cells harbor mutations in p53, contributing to defects in apoptotic pathways and drug resistance. However, cisplatin-induced apoptosis can also occur in p53 deficient cells; thus, elucidation of the molecular mechanism involved will potentially yield new strategies to eliminate tumors that have defects in the p53 pathway. Most of the studies in this field have been conducted in cultured mammalian cells, not amenable to systematic genetic manipulation. Therefore, we aimed to establish a simplified model devoid of a p53 ortholog to study cisplatin-induced programmed cell death (PCD), using the yeast Saccharomyces cerevisiae.Our results indicate cisplatin induces an active form of cell death in yeast, as this process was partially dependent on de novo protein synthesis and did not lead to loss of membrane integrity. Cisplatin also increased DNA condensation and fragmentation/degradation, but no significant mitochondrial dysfunction other than partial fragmentation. Co-incubation with the proteasome inhibitor MG132 increased resistance to cisplatin and, accordingly, yeast strains deficient in proteasome activity were more resistant to cisplatin than wild-type strains. Proteasome inhibitors can sensitize tumor cells to cisplatin, but protect others from cisplatin-induced cell death. Our results indicate inhibition of the proteasome protects budding yeast from cisplatin-induced cell death and validate yeast as a model to study the role of the proteasome in cisplatin-induced PCD. Elucidation of this mechanism will aid in the development of new strategies to increase the efficacy of chemotherapy.     

Tempol,a Superoxide Dismutase Mimetic Agent,Ameliorates Cisplatin-Induced Nephrotoxicity through Alleviation of Mitochondrial Dysfunction in Mice

BackgroundMitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice.ConclusionThis study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction.     

Requirement for ERK activation in cisplatin-induced apoptosis

Cisplatin activates multiple signal transduction pathways involved in coordinating cellular responses to stress. Here we demonstrate a requirement for extracellular signal-regulated protein kinase (ERK), a member of the mitogen-activated protein kinase family in mediating cisplatin-induced apoptosis of human cervical carcinoma HeLa cells. Cisplatin treatment resulted in dose- and time- dependent activation of ERK. That elevated ERK activity contributed to cell death by cisplatin was supported by several observations: 1) PD98059 and U0126, chemical inhibitors of the MEK/ERK signaling pathway, prevented apoptosis; 2) pretreatment of cells with TPA, an activator of the ERK pathway, enhanced their sensitivity to cisplatin; 3) suramin, a growth factor receptor antagonist that greatly suppressed ERK activation, likewise inhibited cisplatin-induced apoptosis; and, finally, 4) HeLa cell variants selected for cisplatin resistance showed reduced activation of ERK following cisplatin treatment. Cisplatin-induced apoptosis was associated with cytochrome c release and subsequent caspase-3 activation, both of which could be prevented by treatment with the MEK inhibitors. However, the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone protected HeLa cells against apoptosis without affecting ERK activation. Taken together, our findings suggest that ERK activation plays an active role in mediating cisplatin-induced apoptosis of HeLa cells and functions upstream of caspase activation to initiate the apoptotic signal.     

Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation

Nutlins, the newly developed small molecule antagonists of MDM2, activate p53 and induce apoptosis in cancer cells, offering a novel strategy of chemotherapy. Recent studies have further suggested synergistic effects of nutlins with other chemotherapeutic drugs. However, it is unclear whether nutlins increase or decrease the side effects of these drugs in normal non-malignant cells or tissues. Cisplatin is a widely used chemotherapy drug, which has a major side effect of kidney injury. Here we show that Nutlin-3 protected kidney cells against cisplatin-induced apoptosis. The cytoprotective effects of Nutlin-3 were not related to its regulation of p53 or consequent gene expression during cisplatin treatment. Moreover, the protective effects were shown in MDM2-, MDM4-, or p53-deficient cells. On the other hand, Nutlin-3 suppressed mitochondrial events of apoptosis during cisplatin incubation, including Bax activation and cytochrome c release. Nutlin-3 attenuated cisplatin-induced oligomerization of Bax and Bak but not their interactions with Bcl-XL. In isolated mitochondria, Nutlin-3 inhibited cytochrome c release induced by Ca2+, Bim peptide, and recombinant tBid. Importantly, it blocked both Bax and Bak oligomerization under these conditions. Together, the results have uncovered a new pharmacological function of nutlins, i.e. suppression of Bax and Bak, two critical mediators of apoptosis.     

Cisplatin and Doxorubicin Induce Distinct Mechanisms of Ovarian Follicle Loss; Imatinib Provides Selective Protection Only against Cisplatin

Purpose

Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin) were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined.

Experimental design

Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect.

Results

Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001) and doxorubicin (3 fold, p<0.01). TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01) but not against doxorubicin treatment.

Conclusion

Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s) the patient is exposed to.     

The mode of cisplatin-induced cell death in CYP2E1-overexpressing HepG2 cells: modulation by ERK, ROS, glutathione, and thioredoxin

In a previous study, E47 HepG2 cells that overexpress human CYP2E1 were shown to be more sensitive to cisplatin than C34 cells that do not express CYP2E1. In this study, we found that this sensitivity was due to an earlier activation of ERK in the E47 cells compared to the C34 cells. Glutathione depletion by L-buthionine sulfoximine (BSO) enhanced cisplatin cytotoxicity via increasing production of reactive oxygen species (ROS) and activation of ERK. In contrast, elevation of glutathione by glutathione ethyl ester (GSHE) decreased cisplatin/BSO cytotoxicity by decreasing ROS production and ERK activation. Inhibition of ERK activation by U0126 protected against cisplatin/BSO cytotoxicity via inhibiting ROS production but not restoring intracellular glutathione content. Examination of the mode of cell death showed that U0126 inhibited cisplatin-induced necrosis but not apoptosis. Cisplatin-induced apoptosis was caspases-dependent; BSO switched cisplatin-induced apoptosis to necrosis via decreasing activity of caspases, and GSHE switched cisplatin/BSO-induced necrosis back to apoptosis through maintaining activity of caspases. Similar to GSHE, U0126 partially switched cisplatin/BSO induced necrosis to apoptosis via restoring activity of caspases. Cisplatin lowered levels of thioredoxin, especially in the presence of BSO. Although U0126 failed in restoring intracellular glutathione levels, it restored thioredoxin levels, which maintain the activity of the caspases. These results suggest that thioredoxin can replace glutathione to promote the active thiol redox state necessary for caspase activity, and thus glutathione and thioredoxin regulate the mode of cisplatin toxicity in E47 cells via redox regulation of caspase activity.     

Inhibition of AMP-activated protein kinase sensitizes cancer cells to cisplatin-induced apoptosis via hyper-induction of p53

Cisplatin is one of the most effective and widely used chemotherapeutic agents. However, one of the most salient limitations to the clinical application of cisplatin is the acquired or intrinsic drug resistance exhibited by some tumors. In the present study, we have assessed the potential of an intracellular energy balancing system as a target for augmentation of cisplatin sensitivity in tumors. AMP-activated protein kinase (AMPK) regulates the energy balance system by monitoring intracellular energy status. Here we demonstrate that AMPK is rapidly activated by cisplatin in AGS and HCT116 cancer cells. The inhibition of AMPK in those cells and in xenografts of HCT116 resulted in a remarkable increase in cisplatin-induced apoptosis, which was associated with hyper-induction of the tumor suppressor p53. We further showed that ERK, but not ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) kinases, was involved in the hyper-induction of p53 by the inhibition of cisplatin-induced AMPK. By way of contrast, cisplatin did not induce AMPK activation in HeLa cells, which appear to have a relatively high sensitivity to cisplatin-induced cytotoxicity, but expression of the constitutive active form of AMPK in HeLa cells resulted in a significant increase of cell viability after cisplatin treatment. Collectively, our data suggest that AMPK performs a pivotal function for protection against the cytotoxic effect of cisplatin, thereby implying that AMPK is one of the cellular factors determining the cellular sensitivity to cisplatin. On the basis of these observations, we propose that a strategy combining cisplatin and AMPK inhibition could be developed into a novel chemotherapeutic modality.     

Non-cytotoxic Concentration of Cisplatin Decreases Neuroplasticity-Related Proteins and Neurite Outgrowth Without Affecting the Expression of NGF in PC12 Cells

Cisplatin is the most effective and neurotoxic platinum chemotherapeutic agent. It induces a peripheral neuropathy characterized by distal axonal degeneration that might progress to degeneration of cell bodies and apoptosis. Most symptoms occur nearby distal axonal branches and axonal degeneration might induce peripheral neuropathy regardless neuronal apoptosis. The toxic mechanism of cisplatin has been mainly associated with DNA damage, but cisplatin might also affect neurite outgrowth. Nevertheless, the neurotoxic mechanism of cisplatin remains unclear. We investigated the early effects of cisplatin on axonal plasticity by using non-cytotoxic concentrations of cisplatin and PC12 cells as a model of neurite outgrowth and differentiation. PC12 cells express NGF-receptors (trkA) and respond to NGF by forming neurites, branches and synaptic vesicles. For comparison, we used a neuronal model (SH-SY5Y cells) that does not express trkA nor responds to NGF. Cisplatin did not change NGF expression in PC12 cells and decreased neurite outgrowth in both models, suggesting a NGF/trkA independent mechanism. It also reduced axonal growth (GAP-43) and synaptic (synapsin I and synaptophysin) proteins in PC12 cells, without inducing mitochondrial damage or apoptosis. Therefore, cisplatin might affect axonal plasticity before DNA damage, NGF/trkA down-regulation, mitochondrial damage or neuronal apoptosis. This is the first study to show that neuroplasticity-related proteins might be early targets of the neurotoxic action of cisplatin and their role on cisplatin-induced peripheral neuropathy should be investigated in vivo.     

Interleukin-6 plays a protective role in development of cisplatin-induced acute renal failure through upregulation of anti-oxidative stress factors

AimsCisplatin, a major chemotherapeutic agent, accumulates in proximal tubules of the kidneys and causes acute renal failure dose-dependently. We previously reported that cisplatin induced more severe renal dysfunction in interleukin-6 (IL-6) knockout (IL-6^?/?) mice than in wild-type (WT) mice. Expression of a pro-apoptotic protein was significantly increased with cisplatin in IL-6^?/? mice compared to that in WT mice. IL-6, locally expressed in renal tubular cells after cisplatin administration, prevents the development of renal dysfunction at an early stage. In the present study, we focused on downstream signals of IL-6 and oxidative stress induced by cisplatin in order to evaluate the protective role of IL-6 in the development of acute renal failure.Main methodsWT and IL-6^?/? mice were given either cisplatin (30 mg/kg) or saline intraperitoneally. Blood and kidney samples were collected at 24 h and 72 h after cisplatin administration. The changes in expression of 4-hydroxy-2-nonenal protein (4-HNE, oxidative stress marker) and cyclooxygenase-2 (cox-2), activities of superoxide dismutases and caspase-3, and phosphorylation of extracellular signal-regulated kinase (ERK) were examined.Key findingsCisplatin increased the expression of 4-HNE and cox-2, and phosphorylation of ERK in IL-6^?/? mice than in WT mice. On the other hand, activity of superoxide dismutase, an anti-oxidative enzyme, was significantly decreased in the kidney obtained from IL-6^?/? mice after cisplatin administration.SignificanceOur findings suggest that IL-6 plays a protective role in the development of cisplatin-induced acute renal failure through upregulation of anti-oxidative stress factors.     

Puerarin attenuates cisplatin-induced apoptosis of hair cells through the mitochondrial apoptotic pathway

Puerarin, one of the main components of Pueraria lobata, has been reported to possess a wide range of pharmacological activities, including anti-inflammatory, antioxidative and anti-apoptotic effects. However, the role of puerarin in ototoxic drug-induced hair cell injury has not been well characterized. This study explored whether puerarin protects against cisplatin-induced hair cell damage and its potential mechanisms. The viability of puerarin-treated HEI-OC1 cells was assessed by CCK8 assay. Reactive oxygen species (ROS) was estimated with flow cytometric analysis using Cellrox Green fluorescent probe. Apoptosis-related protein levels were detected by western blot analysis. Immunostaining of the organ of Corti was performed to determine mice cochlear hair cell survival. Our results showed that puerarin improved cell viability and suppressed apoptosis in the cisplatin-damaged HEI-OC1 cells and cochlear hair cells. Mechanistic studies revealed that puerarin attenuated mitochondrial apoptosis pathway by regulating apoptotic related proteins, such as Bax and cleaved caspase-3, and attenuated ROS accumulation after cisplatin damage. Moreover, puerarin was involved in regulating the Akt pathway in HEI-OC1 cells in response to cisplatin. Our results demonstrated that puerarin administration decreased the sensitivity to apoptosis dependent on the mitochondrial apoptotic pathway by reducing ROS generation, which could be used as a new protective agent against cisplatin-induced ototoxicity.     

Endogenous Interleukin 6 Conveys Resistance to cis-Diamminedichloroplatinum-Mediated Apoptosis of the K562 Human Leukemic Cell Line

Cisplatin is an effective chemotherapeutic agent that elicits its antineoplastic activity by binding to DNA and disrupting template functions. IL-6 is a cytokine which has been shown to play a central role in host immunological defense mechanisms. Although K562 leukemic cells have been shown to secrete IL-6, little is known of whether there exists a correlation between the expression of IL-6 and the resistance of these cells to anticancer chemotherapeutic agents. To determine the contribution of IL-6 to the regulation of cisplatin-induced apoptosis in K562 cells, we examined whether treatment of K562 cells and cisplatin-resistant K562 subclones with anti-IL-6 mAb enhances their sensitivity to cisplatin. The results show that cis-diamminedichloroplatinum (CDDP) resistance was overcome by treatment with nontoxic doses of CDDP in combination with anti-IL-6 mAb. When we tested if the synergistic effect of anti-IL-6 and cisplatin could restore the ability of K562 mutant cells to undergo apoptosis, we found the typical DNA laddering in these cells, even in the presence of a nontoxic dose of the drug. Treatment of cells with anti-IL-6 reduced the levels of glutathione. The current studies show that anti-IL-6 mAb sensitized CDDP-resistant K562 cells to CDDP by induction of apoptotic death and the reduction of glutathione levels might be implicated in the enhanced cytotoxicity observed.     

Overexpression of XIAP inhibits cisplatin-induced hair cell loss

Cisplatin is a platinum-containing drug with ototoxicity commonly used clinically and has significant efficacy against a variety of solid tumors. One of the most important mechanisms of ototoxicity is that cisplatin induces apoptosis of hair cells. According to relevant literature, X-linked inhibitor of apoptosis protein (XIAP, anti-apoptotic protein) could inhibit the apoptotic pathway. We hypothesized that this protein might protect cochlear hair cells from cisplatin-induced injury. To figure it out, we treated cochlea of normal mice with various concentrations of cisplatin to observe the response and morphology of hair cells and determine a reasonable concentration. Next, Western Blot and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) experiments were conducted to make an investigation about the expression of XIAP protein and mRNA. In addition, we constructed and identified XIAP overexpressing mice. Finally, we treated cochlear tissues of normal and overexpressing mice with cisplatin to investigate the cyto-protection of XIAP on hair cells, respectively. It was found that 50 μmol/L cisplatin resulted in significant loss and disorganization of hair cells, while simultaneously downregulating the protein and mRNA of XIAP. In XIAP overexpressing mice, the loss and disorganization of hair cells were significantly lessened. These results showed that XIAP can lessen cisplatin-induced hair cell loss and play a role in otoprotection.     

SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53

Nephrotoxicity is one of the important dose-limiting factors during cisplatin treatment. There is a growing body of evidence that activation of p53 has a critical role in cisplatin-induced renal apoptotic injury. The nicotinamide adenine dinucleotide-dependent protein deacetylase SIRT1 decreases apoptosis through deacetylating of p53, and resveratrol is known as an activator of SIRT1. To study the role of SIRT1 in cisplatin-induced renal injury through interaction with p53, mouse proximal tubular cells (MPT) were treated with cisplatin and examined the expression level of SIRT1, acetylation of p53, PUMA-α, Bax, the cytosolic/mitochondrial cytochrome c ratio, and active caspase-3. The expression of SIRT1 was decreased by cisplatin. Resveratrol, a SIRT1 activator, ameliorated cisplatin-induced acetylation of p53, apoptosis, and cytotoxicity in MPT cells. In addition, resveratrol remarkably blocked cisplatin-induced decrease of Bcl-xL in MPT cells. Further specific SIRT1 inhibition with EX 527 or small interference RNA specific to SIRT1 reversed the effect of resveratrol on cisplatin-induced toxicity. Inhibition of p53 by pifithrin-α reversed the effect of EX527 in protein expression of PUMA-α, Bcl-xL, and caspase-3 and cytotoxicity in MPT cells. SIRT1 protein expression after cisplatin treatment was significantly decreased in the kidney. SIRT1 activation by resveratrol decreased cisplatin-induced apoptosis while improving the glomerular filtration rate. Taken together, our findings suggest that the modulation of p53 by SIRT1 could be a possible target to attenuate cisplatin-induced kidney injury.