Ursolic acid protects against cisplatin-induced ototoxicity by inhibiting oxidative stress and TRPV1-mediated Ca2+-signaling

Cisplatin (CDDP) is widely used in clinical settings for the treatment of various cancers. However, ototoxicity is a major side effect of CDDP, and there is an associated risk of irreversible hearing loss. We previously demonstrated that CDDP could induce ototoxicity via activation of the transient receptor potential vanilloid receptor 1 (TRPV1) pathway and subsequent induction of oxidative stress. The present study investigated whether ursolic acid (UA) treatment could protect against CDDP-induced ototoxicity. UA is a triterpenoid with strong antioxidant activity widely used in China for the treatment of liver diseases. This traditional Chinese medicine is mainly isolated from bearberry, a Chinese herb. The present results showed that CDDP increased auditory brainstem response threshold shifts in frequencies associated with observed damage to the outer hair cells. Moreover, CDDP increased the expression of TRPV1, calpain 2 and caspase-3 in the cochlea, and the levels of Ca(2+)and 4-hydroxynonenal. UA co-treatment significantly attenuated CDDP-induced hearing loss and inhibited TRPV1 pathway activation. In addition, UA enhanced CDDP-induced growth inhibition in the human ovarian cancer cell line SKOV3, suggesting that UA synergizes with CDDPin vitro. Collectively, the present data suggested that UA could effectively attenuate CDDP-induced hearing loss by inhibiting the TRPV1/Ca2+/calpain-oxidative stress pathway without impairing the antitumor effects of CDDP.