Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defence.

Bidya Dhar Sahu,Ramakrishna Sistla,Shyam Sunder Rachamalla,Meghana Koneru,Jerald Mahesh Kumar,Madhusudana Kuncha,Anil Kumar Kalvala,Partha Mukhopadhyay

doi:10.1371/journal.pone.0105070

Abstract

Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine); degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65) nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use.

Highlights

Though recent investigations find the new generation of platinum-based cytotoxic agents, cisplatin remains a highly effective and widely used anti-neoplastic drug against various solid tumors, including endometrial, testicular, ovarian, breast, bladder, head, neck and lung cancer [1]
We demonstrated that fisetin treatment along with cisplatin largely reduced the nephrotoxicity, a clinical-utility limiting side effect of the cisplatin chemotherapy, by employing rat model
The findings of the present study revealed that fisetin treatment reduced the cisplatin-induced renal and mitochondrial oxidative stress, restored mitochondrial respiratory enzyme activities and attenuated expressions of apoptosis and inflammation related proteins, forming the molecular basis for protective mechanism of fisetin against cisplatin-induced nephrotoxicity

Summary

Introduction

Though recent investigations find the new generation of platinum-based cytotoxic agents, cisplatin (cis-Diamminedichloroplatinum II, CDDP) remains a highly effective and widely used anti-neoplastic drug against various solid tumors, including endometrial, testicular, ovarian, breast, bladder, head, neck and lung cancer [1]. Many studies, including ours, have demonstrated that oxidative stress due to impaired antioxidant status and/or excess generation of free radicals, in particular superoxide, due to cisplatin-induced renal NADPH oxidase NOX4 (RENOX) and phagocyte NADPH oxidase (NOX2/ gp91phox) over expression is involved in such deleterious effects [2,3]. Evidences from in vitro and in vivo studies have demonstrated that cisplatin induces apoptosis and necrosis of renal tubular cells through activation of both intrinsic and extrinsic mitochondrial pathways [4,5]. Activation of pro-inflammatory pathways (TNF-a, NF-kB) and infiltration of inflammatory cells are the other crucial mechanisms involved in cisplatin-induced nephrotoxicity [8]. A growing body of evidence suggests the mitochondrial dysfunction, generation of mitochondrial reactive oxygen species (ROS) and impairment of mitochondrial antioxidant activities trigger the deleterious cascade of renal tissue injury in cisplatin administered rats [9,10]

Methods

Results

Conclusion