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Abstract：
Capsaicin (CAP) exerts significant anti-tumor effects on a variety of tumors, with low intrinsic toxicity. Cisplatin (DDP) is currently the first-line drug for the treatment of oral cancer; however, its clinical efficacy is impeded by chemoresistance and negligible side effects. Whether the combined use of CAP and DDP has a synergistic antitumor effect on tongue squamous cell carcinoma (TSCC) cells and its underlying mechanisms remains unclear. The present study revealed that CAP reduced the activity of TSCC cells in a dose- and time-dependent manner. We also observed changes in the mitochondrial functional structure of TSCC cells, along with the induction of mitochondrial apoptosis. Moreover, when CAP was combined with DDP, a synergistic cytotoxic effect on TSCC cells was observed, which had a significant impact on inducing apoptosis, inhibiting proliferation, and disrupting the mitochondrial membrane potential in TSCC cells compared to the single-drug treatment and control groups. These effects are associated with TRPV1, a high-affinity CAP receptor. The combined use of CAP and DDP can activate the TRPV1 receptor, resulting in intracellular Ca2+ overload and activation of the calpain pathway, ultimately leading to mitochondrial apoptosis. This potential mechanism was validated in TSCC xenograft models. In conclusion, our findings clearly demonstrate that CAP exerts synergistic pro-apoptotic effects with DDP in TSCC through the calpain pathway mediated by TRPV1. Thus, CAP can be considered an effective adjuvant drug for DDP in the treatment of TSCC.
摘要：
辣椒素(CAP)对多种肿瘤具有显著的抗肿瘤作用,具有低的内在毒性。顺铂（DDP）是目前治疗口腔癌的一线药物；然而，它的临床疗效受到化学耐药性和可忽略的副作用的阻碍。CAP和DDP联合使用是否对舌鳞状细胞癌（TSCC）细胞具有协同抗肿瘤作用及其潜在机制尚不清楚。本研究表明，CAP以剂量和时间依赖性方式降低了TSCC细胞的活性。我们还观察到TSCC细胞的线粒体功能结构的变化，随着线粒体凋亡的诱导。此外，当CAP与DDP结合使用时，观察到对TSCC细胞的协同细胞毒性作用，对诱导细胞凋亡有重大影响，抑制增殖，与单药治疗组和对照组相比，破坏了TSCC细胞的线粒体膜电位。这些作用与高亲和力CAP受体TRPV1有关。联合使用CAP和DDP可以激活TRPV1受体，导致细胞内Ca2+过载和钙蛋白酶途径的激活，最终导致线粒体凋亡。这种潜在的机制在TSCC异种移植模型中得到验证。总之,我们的研究结果清楚地表明，CAP通过TRPV1介导的钙蛋白酶途径在TSCC中与DDP发挥协同促凋亡作用。因此，CAP可以被认为是治疗TSCC的DDP的有效辅助药物。
