Cilostazol attenuates cisplatin-induced acute liver injury by targeting the SIRT1/AMPK/PGC-1α signaling pathway, with an impact on miRNA-34a

Abstract

The dominant chemotherapeutic agent, cisplatin (CP), is widely used to manage various cancer types. Despite its effectiveness, CP use is associated with severe hepatotoxicity. Cilostazol (CSZ), a selective phosphodiesterase III inhibitor, has recently demonstrated remarkable anti-inflammatory and anti-apoptotic properties in different diseases. Additionally, it exhibits hepatoprotective effects against various forms of liver injury. Hence, this study aimed to assess the potential hepatoprotective and ameliorative effects of CSZ on CP-induced acute liver injury (ALI) and to elucidate the underlying molecular mechanisms. To achieve this, ALI was induced by a single injection of CP (20 mg/kg; i.p.) in male Wistar rats pretreated with CSZ (5 or 10 mg/kg) administered orally for one week. The findings revealed that CSZ effectively reversed CP-induced hepatic dysfunction, as evidenced by notable liver function tests and improvements in histological examination. Additionally, CSZ protected against CP-mediated liver oxidative stress by decreasing MDA levels while increasing GSH and GPx levels and enhancing SOD activity. Furthermore, CSZ exhibited a potent anti-inflammatory effect, reducing the expression of pro-inflammatory cytokines, including NF-κB, IL-1β, and TNF-α. Regarding hepatocyte apoptosis, CSZ suppressed Bax immunoexpression and caspase-3 and caspase-9 levels while enhancing Bcl-2 expression, thereby mitigating hepatic cell death. The hepatoprotective effects of CSZ could be attributed to the regulation of the miRNA-34a/AMPK/SIRT1/PGC-1α signaling pathway, leading to the activation of the Nrf2/HO-1-mediated antioxidative defense mechanism. In conclusion, CSZ could be a promising therapeutic agent for preventing CP-induced ALI, potentially improving the quality of life for cancer patients.