Dichloroacetate enhances the anti-tumor effect of sorafenib via modulating the ROS-JNK-Mcl-1 pathway in liver cancer cells
Dichloroacetate enhances the anti-tumor effect of sorafenib via modulating the ROS-JNK-Mcl-1 pathway in liver cancer cells
复制标题
二氯乙酸通过调节肝癌细胞中ROS-JNK-Mcl-1通路增强索拉非尼的抗肿瘤作用
DOI：
10.1016/j.yexcr.2021.112755
复制
发表时间：
2021-08-03
影响因子：
3.7
通讯作者：
Lian, Jiqin
中科院分区：
文献类型：
--
作者：
Sun, Liangbo;Jiang, Yangzhou;Lian, Jiqin
肝癌是最常见、复发率最高的恶性肿瘤之一。除了放疗和手术外，化疗在肝癌的治疗中也发挥着至关重要的作用。索拉非尼和以索拉非尼为基础的联合疗法已被证明对肿瘤有效。然而，以往的临床研究表明，部分肝癌患者对索拉非尼治疗产生耐药，现有的策略在临床上并不令人满意。因此，迫切需要研究提高索拉非尼治疗肝癌的有效性的策略，并探索有效的药物组合。在本研究中，我们发现二氯乙酸盐（DCA）可以显著增强索拉非尼对肝癌细胞的抗肿瘤作用，包括降低肝癌细胞的存活率和显著促进肝癌细胞的凋亡。此外，与单独索拉非尼相比，DCA和索拉非尼的组合通过增强抗凋亡蛋白Mcl-1的磷酸化而显著增加其降解。过表达Mcl-1可显著减弱DCA和索拉非尼诱导肝癌细胞凋亡的协同作用。此外，我们发现DCA联合索拉非尼组的ROS-JNK通路明显激活。ROS和p-JNK水平在两个药物组合组中显著上调。抗氧化剂NAC可以减轻DCA和索拉非尼对ROS产生、JNK激活、Mcl-1降解和细胞凋亡的协同作用。此外，DCA和索拉非尼对Mcl-1降解和凋亡的影响也可被JNK抑制剂“SP”600125抑制。最后，DCA和索拉非尼的协同作用，抑制肿瘤生长，Mcl-1降解和诱导细胞凋亡，在体内的肝癌异种移植也被验证。这些发现表明DCA通过肝癌细胞中的ROS-JNK-Mcl-1通路增强索拉非尼的抗肿瘤作用。本研究为提高索拉非尼的化疗效果提供了新的思路，为索拉非尼在肝癌治疗中的进一步临床应用提供了参考。
Liver cancer is one of the most common and high recurrence malignancies. Besides radiotherapy and surgery, chemotherapy also plays an essential role in the treatment of liver cancer. Sorafenib and sorafenib-based combination therapies have been proven efficacy against tumors. However, previous clinical studies have indicated that some patients with liver cancer are resistant to sorafenib treatment and the existing strategies are not satisfactory in the clinic. Therefore, it is urgent to investigate strategies to improve the effectiveness of sorafenib for liver cancer and to explore effective drug combinations. In the present study, we found that dichloroacetate (DCA) could significantly enhance the anti-tumor effect of sorafenib on liver cancer cells, including reduced viability and dramatically promoted apoptosis in liver cancer cells. Moreover, compared to sorafenib alone, the combination of DCA and sorafenib markedly increased the degradation of anti-apoptotic protein Mcl-1 by enhancing its phosphorylation. Overexpression of Mcl-1 could significantly attenuate the synergetic effect of DCA and sorafenib on apoptosis induction in liver cancer cells. Furthermore, we found that the ROS-JNK pathway was obviously activated in the DCA combined sorafenib group. The levels of ROS and p-JNK were dramatically upregulated in the two drug combination groups. Antioxidant NAC could alleviate the synergetic effects of DCA and sorafenib on ROS generation, JNK activation, Mcl-1 degradation, and cell apoptosis. Moreover, DCA and sorafenib's effects on Mcl-1 degradation and apoptosis could also be inhibited by JNK inhibitor 'SP' 600125. Finally, the synergetic effects of DCA and sorafenib on tumor growth suppression, Mcl-1 degradation and induction of apoptosis were also validated in liver cancer xenograft in vivo. These findings indicate that DCA enhances the anti-tumor effect of sorafenib via the ROS-JNK-Mcl-1 pathway in liver cancer cells. This study may provide new insights to improve the chemotherapeutic effect of sorafenib, which may be beneficial for further clinical application of sorafenib in liver cancer treatment.