Quinacrine ameliorated Cisplatin‐induced renal toxicity via modulation of Sirtuin‐1 and its downstream inflammatory and apoptosis pathways

Abstract

Cisplatin is an effective and widely used chemotherapeutic agent, while underlying renal toxicity is a major limitation for its use. Quinacrine, is an FDA approved antimalarial agent that is known for its anti-inflammatory effect. It has been shown that quinacrine is therapeutically beneficial in cancer, lupus erythematosus and cutaneous sarcoidosis, however, its use to protect against cisplatin toxicity has not been investigated. In this study, we investigated the ameliorative effect of quinacrine against cisplatin induced renal toxicity in rats and the potential molecular mechanism of quinacrine action. Cisplatin toxicity was induced by a single intraperitoneal injection of 10 mg/kg at day 5. Reno protective effect of quinacrine was assessed by intraperitoneal injection of 10 mg/kg/day for the whole-time course of the experiment (10 days). Quinacrine increased rats’ survival rate from 50% (cisplatin group) to 87.5%, with significant decrease in relative kidney weight to body weight, serum creatinine and urea levels in addition to significant reduction in renal tissue fibrosis compared with cisplatin group. Moreover, quinacrine attenuated cisplatin-induced oxidative stress upregulation as indicated by significant decrease in renal malondialdehyde concentration and significant increase in renal total antioxidant capacity compared with cisplatin group. Mechanistically, quinacrine significantly upregulated renal tissue concentration of sirtuin-1 (Sirt-1) which significantly downregulated the inflammatory markers: Intercellular Adhesion Molecule-1 (ICAM-1) and tumor necrosis factor-α (TNF-α). In addition, quinacrine significantly prevented cisplatin-induced apoptosis as evident by decreased renal tissue expression of caspases (1, 3, 8 and 9), decreased the apoptotic proteins BAX and P53 and increased the anti-apoptotic protein BCL2 compared with cisplatin group. Altogether, this study proposes, for the first time, that quinacrine ameliorated cisplatin-induced renal toxicity via upregulation of Sirt-1, downregulation of inflammatory markers (ICAM-1 and TNF-α), restoring oxidative balance and suppressing apoptosis.