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 up-regulated 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.

肝癌是最常见且复发率高的恶性肿瘤之一。除了放疗和手术外，化疗在肝癌的治疗中也发挥着重要作用。索拉非尼和基于索拉非尼的联合疗法已被证明对肿瘤有效。然而，既往临床研究表明，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疗效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（DCA）可以显着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活力并显着促进肝癌细胞的凋亡。此外，与单独使用索拉非尼相比，DCA和索拉非尼的组合通过增强抗凋亡蛋白Mcl-1的磷酸化而显着增加其降解。 Mcl-1的过表达可以显着减弱DCA和索拉非尼对肝癌细胞凋亡诱导的协同作用。此外，我们发现DCA联合索拉非尼组中ROS-JNK通路明显激活。两个药物组合组中 ROS 和 p-JNK 的水平显着上调。抗氧化剂NAC可以减轻DCA和索拉非尼对ROS生成、JNK激活、Mcl-1降解和细胞凋亡的协同作用。此外，JNK 抑制剂“SP”600125 也可以抑制 DCA 和索拉非尼对 Mcl-1 降解和细胞凋亡的影响。 最后，DCA和索拉非尼对肿瘤生长抑制、Mcl-1降解和诱导细胞凋亡的协同作用也在肝癌异种移植体内得到验证。这些发现表明，DCA 通过 ROS-JNK-Mcl-1 通路增强肝癌细胞中索拉非尼的抗肿瘤作用。该研究可能为提高索拉非尼的化疗效果提供新的见解，这可能有利于索拉非尼在肝癌治疗中的进一步临床应用。