Ursolic acid protects against cisplatin-induced ototoxicity by inhibiting oxidative stress and TRPV1-mediated Ca2+-signaling
Ursolic acid protects against cisplatin-induced ototoxicity by inhibiting oxidative stress and TRPV1-mediated Ca2+-signaling
复制标题
熊果酸通过抑制氧化应激和 TRPV1 介导的 Ca2 信号传导来防止顺铂诱导的耳毒性
DOI：
10.3892/ijmm.2020.4633
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发表时间：
2020-08-01
影响因子：
5.4
通讯作者：
Wang, Aimei
中科院分区：
文献类型：
--
作者：
Di, Yang;Xu, Tao;Wang, Aimei
顺铂（CDDP）广泛用于治疗各种癌症的临床环境中。然而，耳毒性是CDDP的主要副作用，并且存在不可逆听力损失的相关风险。我们以前证明，CDDP可以通过激活瞬时受体电位香草酸受体1（TRPV 1）途径和随后诱导氧化应激诱导耳毒性。本研究探讨熊果酸（UA）治疗是否可以保护CDDP诱导的耳毒性。UA是一种具有较强抗氧化活性的三萜类化合物，在我国被广泛应用于肝脏疾病的治疗。本实验结果表明，CDDP可增加听性脑干反应阈移频率，这与观察到的外毛细胞损伤有关。CDDP还可增加耳蜗TRPV 1、calpain 2和caspase-3的表达，并增加Ca（2+）和4-羟基壬烯醛的含量。UA联合治疗显著减轻CDDP诱导的听力损失，并抑制TRPV 1通路的激活。此外，UA增强CDDP诱导的人卵巢癌细胞系SKOV 3的生长抑制，表明UA与CDDP体外协同作用。总的来说，目前的数据表明，UA可以有效地减轻CDDP诱导的听力损失，通过抑制TRPV 1/Ca 2 +/钙蛋白酶-氧化应激途径，而不损害CDDP的抗肿瘤作用。
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.