Phosphorylation of c-Jun N-terminal Kinases (JNKs) is involved in the preventive effect of xanthorrhizol on cisplatin-induced hepatotoxicity

Abstract

Cisplatin is a potent anti-cancer chemotherapeutic agent but has the undesirable side effect of hepatotoxicity at high doses. In a previous study, abrogation of cisplatin-induced hepatotoxicity by pretreatment with xanthorrhizol was observed in mice, but the mechanism has not yet been studied. We therefore investigated whether the protective effect of xanthorrhizol on cisplatin-induced hepatotoxicity is associated with the mitogen-activated protein (MAP) kinase-signaling pathway. Cisplatin caused phosphorylation of both c-Jun N-terminal kinases 1/2 (JNK1/2) and the extracellular signal-regulated kinase 1/2 (ERK1/2), but not that of p38. However, cisplatin-induced phosphorylation of JNKs, especially JNK1, was highly attenuated by pretreatment with xanthorrhizol in a dose-dependent manner. This study suggested that the phosphorylation of JNKs could be involved in the protective effect of xanthorrhizol on cisplatin-induced hepatotoxicity and it also affects gene transcription by regulating the expression of transcription factor subunits such as c-fos and p50 in part. In addition, considering that the expression of both cytochrome c and caspase-9 were not changed in this model, its mechanism might be independent of mitochondria-related apoptosis. This is the first report giving evidence that the physiological function of xanthorrhizol is linked to regulation of the phosphorylation of JNK(s).