Ameliorative Effect of Fisetin on Cisplatin-Induced Nephrotoxicity in Rats via Modulation of NF-κB Activation and Antioxidant Defence

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.

Design and development of dry powder sulfobutylether-β-cyclodextrin complex for pulmonary delivery of fisetin

“…It has shown synergistic activities with other anticancer agents (i.e. cisplatin and cyclophosphamide) in different carcinoma cell lines [2,3] and acts as an adjunct in cancer therapy to alleviate specific adverse effects related to cytotoxic agents or other therapeutics, including protection against ovariectomy-induced bone loss in mice [4] and has a renoprotective effect in cisplatininduced nephrotoxicity in rats [5].…”

Paeonol alleviates epirubicin-induced renal injury in mice by regulating Nrf2 and NF-κB pathways

“…The proposed mechanism of anthracycline-induced organ damage includes the generation of reactive oxygen species, inflammation, caspase activation and apoptosis (Sahu et al, 2014(Sahu et al, , 2015. Our previous research has suggested that the activation of the nuclear factor-κB (NF-κB) pathway is involved in the development and progression of epirubicin-induced hepatotoxicity and reactive oxygen species play a crucial role in aggravating inflammation by activating the NF-κB pathway (Wu et al, 2016).…”

Evaluating the ameliorative potential of plant flavonoids and their nanocomposites in bleomycin induced idiopathic pulmonary fibrosis

“…It has been reported that, fisetin inhibits LPS)-induced pro-inflammatory cytokine release and also activation of macrophages (Kim et al, 2012;Liu et al, 2010). Fisetin also showed its antidepressant properties (Sahu et al, 2014).…”