Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation
Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation
复制标题
双去甲氧基姜黄素通过自噬激活减轻凡德他尼引起的体内和体外皮肤毒性
DOI：
10.1016/j.biopha.2021.112297
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发表时间：
2021
影响因子：
7.5
通讯作者：
Luo Peihua
中科院分区：
文献类型：
--
作者：
Jin Ying;Chen Xueqin;Gao Zizheng;Shen Xiaofei;Fu Huangxi;Pan Zezheng;Yan Hao;Yang Bo;He Qiaojun;Xu Zhifei;Luo Peihua
凡德他尼是一种多靶点激酶抑制剂，适用于治疗不可切除的甲状腺髓样癌，在临床使用期间报告了皮肤毒性的高发生率，范围为29.2%至71.2%。凡德他尼的皮肤毒性限制了其临床获益，但其潜在机制和保护策略尚未得到充分研究。因此，我们首先建立了一个动物体内模型，以55 mg/kg/d的剂量连续给药C57 BL/6 21 d，并验证了凡德他尼在体内可以诱导皮肤皮疹，这与临床研究一致。我们进一步培养了HaCaT和NHEK细胞（永生化或原代人类角质形成细胞系），并研究了凡德他尼（0-10 μM，0-24小时）引起的细胞生存和死亡过程的改变。western blot结果显示，凋亡相关蛋白、c-PARP、c-Caspase 3和Bax表达水平升高，抗凋亡蛋白Bcl 2和MCL 1表达水平降低。同时，凡德他尼下调线粒体膜电位，从而导致细胞色素C的释放，活性氧的过量产生和DNA损伤。此外，我们发现5 μM双脱甲氧基姜黄素通过激活体内和体外自噬部分挽救了凡德他尼诱导的线粒体途径依赖性角质形成细胞凋亡，从而减轻了皮肤毒性。结论：我们的研究揭示了在皮肤毒性发生过程中凡德他尼诱导角质形成细胞凋亡的机制，并建议双脱甲氧基姜黄素作为一种潜在的保护药物。这项工作为治疗凡德他尼诱导的皮肤毒性提供了一种潜在的有前途的治疗策略。
High incidence of cutaneous toxicity ranging from 29.2% to 71.2% has been reported during clinical use of vandetanib, which is a multi-target kinase inhibitor indicated for the treatment of unresectable medullary thyroid carcinoma. The cutaneous toxicity of vandetanib has limited its clinical benefits, but the underlying mechanisms and protective strategies are not well studied. Hence, we firstly established anin vivomodel by continuously administrating vandetanib at 55 mg/kg/day to C57BL/6 for 21 days and verified that vandetanib could induce skin rashin vivo, which was consistent with the clinical study. We further cultured HaCaT and NHEK cells, the immortalized or primary human keratinocyte line, and investigated vandetanib (0–10 μM, 0–24 h)-caused alteration in cellular survival and death processes. The western blot showed that the expression level of apoptotic-related protein, c-PARP, c-Caspase 3 and Bax were increased, while the anti-apoptotic protein Bcl2 and MCL1 level were decreased. Meanwhile, vandetanib downregulated mitochondrial membrane potential which in turn caused the release of Cytochrome C, excessive production of reactive oxygen species and DNA damage. Furthermore, we found that 5 μM bisdemethoxycurcumin partially rescued vandetanib-induced mitochondria pathway-dependent keratinocyte apoptosis via activation of autophagyin vivoandin vitro, thereby ameliorated cutaneous toxicity. Conclusively, our study revealed the mechanisms of vandetanib-induced apoptosis in keratinocytes during the occurrence of cutaneous toxicity, and suggested bisdemethoxycurcumin as a potential protective drug. This work provided a potentially promising therapeutic strategy for the treatment of vandetanib-induced cutaneous toxicity.