Abstract：
Cisplatin is commonly used for the chemotherapy of tongue squamous cell carcinoma (TSCC); however, adverse side effects and drug resistance impact its therapeutic efficacy. Capsaicin is an active ingredient in chili peppers that exerts antitumor effects, whether it exerts antitumor effects on cisplatin-resistant cells remains unknown. Therefore, in this study, we investigated the effect of capsaicin on cisplatin resistance in TSCC cells and explored the underlying mechanisms. A cisplatin-resistant TSCC cell line was established by treated with increasing cisplatin concentrations. Combined treatment with cisplatin and capsaicin decreased the glucose consumption and lactate dehydrogenase activity and increased the adenosine triphosphate production both in vitro and in vivo, suggesting the inhibition of the Warburg effect. Moreover, this combined treatment induced cell apoptosis and significantly upregulated the levels of proapoptotic proteins, such as Bax, cleaved caspase-3, -7, and -9, and apoptosis-inducing factor. In contrast, levels of the antiapoptotic protein, Bcl-2, were downregulated. Additionally, LKB1 and AMPK activities were stimulated, whereas those of AKT and mTOR were suppressed. Notably, AMPK knockdown abolished the inhibitory effects of capsaicin and cisplatin on the AKT/mTOR signaling pathway and Warburg effect. Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis. Our findings suggest combination therapy with capsaicin and cisplatin as a potentially novel strategy and highlight capsaicin as a promising adjuvant drug for TSCC treatment.
摘要：
顺铂通常用于舌鳞状细胞癌（TSCC）的化疗；然而，副作用和耐药性影响其治疗效果。辣椒素是辣椒中的一种活性成分，具有抗肿瘤作用，其是否对顺铂耐药细胞具有抗肿瘤作用尚不清楚.因此,在这项研究中，我们研究了辣椒素对TSCC细胞顺铂耐药的影响，并探讨了潜在的机制。通过用增加的顺铂浓度处理来建立顺铂抗性TSCC细胞系。顺铂和辣椒素联合治疗降低了葡萄糖消耗和乳酸脱氢酶活性，并增加了体外和体内三磷酸腺苷的产生。表明Warburg效应的抑制作用.此外，这种联合治疗诱导细胞凋亡并显著上调促凋亡蛋白的水平，比如Bax,裂解的caspase-3、-7和-9，以及凋亡诱导因子。相比之下,抗凋亡蛋白的水平，Bcl-2下调。此外,LKB1和AMPK活性被刺激，而AKT和mTOR的抑制。值得注意的是,AMPK敲除消除了辣椒素和顺铂对AKT/mTOR信号通路的抑制作用和Warburg效应。总的来说,辣椒素和顺铂联合治疗通过抑制Warburg效应并通过AMPK/AKT/mTOR轴促进线粒体依赖性细胞凋亡,逆转顺铂耐药.我们的研究结果表明，辣椒素和顺铂的联合治疗是一种潜在的新策略，并强调辣椒素是TSCC治疗的有前途的辅助药物。
