Department of Clinical Biochemistry, Army Medical University (Third Military Medical University), Chongqing 400038, China.
Department of Educational College, Chongqing Normal University, Chongqing 400047, China.
Biochem Pharmacol. 2023 May;211:115538. doi: 10.1016/j.bcp.2023.115538. Epub 2023 Apr 3.
Liver cancer is the most common and frequentlyoccurring cancer. In addition to radiotherapy, chemotherapy and surgery are recommended as part of liver cancer treatment. The efficacy of sorafenib and sorafenib-based combination treatment against tumors has been verified. Although, clinical trials have revealed that some individuals are not sensitive to sorafenib therapy, and current therapeutic approaches are ineffective. Consequently, it is urgent to explore effective drug combinations and innovative techniques for increasing the effectiveness of sorafenib in the curing of liver tumor. Herein, we show that dihydroergotamine mesylate (DHE), an anti-migraine agent, could effectively suppress liver cancer cells proliferation by inhibiting STAT3 activation. However, DHE can enhance the protein stability of Mcl-1 by activating ERK, making DHE less effective in apoptosis induction. Specifically, DHE enhances the effects of sorafenib on liver cancer cells, such as decreased viability and increased apoptosis. Furthermore, the mixture of sorafenib and DHE could enhance DHE-triggered STAT3 suppression and inhibit DHE-mediated ERK-Mcl-1 pathway activation. In vivo, the combination of sorafenib with DHE produced a substantial synergy in suppressing tumour growth and causing apoptosis, ERK inhibition and Mcl-1 degradation. These findings suggest that DHE can effectively inhibit cell proliferation and enhance sorafenib anti-cancer activity in liver cancer cells. The current study provides some new insights that DHE asa novel anti-liver cancer therapeutic agent has been shown to improve treatment outcomes of sorafenib, which might be helpful in order to advance sorafenib in liver cancer therapeutics.
肝癌是最常见和最常发生的癌症。除了放疗，化疗和手术也被推荐作为肝癌治疗的一部分。索拉非尼和索拉非尼为基础的联合治疗对肿瘤的疗效已经得到了验证。然而，临床试验表明，一些人对索拉非尼治疗不敏感，目前的治疗方法无效。因此，迫切需要探索有效的药物组合和创新技术，以提高索拉非尼在治疗肝癌中的疗效。在这里，我们表明三甲氢麦角胺（DHE），一种偏头痛治疗药物，可以通过抑制 STAT3 激活有效地抑制肝癌细胞增殖。然而，DHE 通过激活 ERK 可以增强 Mcl-1 的蛋白稳定性，从而降低 DHE 在诱导凋亡方面的效果。具体来说，DHE 增强了索拉非尼对肝癌细胞的作用，如降低活力和增加凋亡。此外，索拉非尼和 DHE 的混合物可以增强 DHE 触发的 STAT3 抑制，并抑制 DHE 介导的 ERK-Mcl-1 通路激活。在体内，索拉非尼与 DHE 的联合使用在抑制肿瘤生长和诱导细胞凋亡、ERK 抑制和 Mcl-1 降解方面产生了显著的协同作用。这些发现表明，DHE 可以有效地抑制肝癌细胞的增殖，并增强索拉非尼的抗癌活性。本研究提供了一些新的见解，即 DHE 作为一种新型的肝癌治疗药物，可以提高索拉非尼的治疗效果，这可能有助于推进索拉非尼在肝癌治疗中的应用。
