Sorafenib, a small inhibitor of tyrosine protein kinases, is currently the standard chemotherapy drug for the treatment of advanced hepatocellular carcinoma (HCC). Although sorafenib improves the survival of HCC patients, its efficacy is not optimal and requires further improvement. Capsaicin, the major active component of chili peppers from the genus Capsicum, is not only the agonist of TRPV1 channel, but also displays antitumor activity and enhances the sensitivity of cancer cells to cytotoxic drugs. In this study, we investigated the antitumor effects of combined sorafenib and capsaicin on HCC cells in vitro and xenograft tumors. Treatment with capsaicin alone dose-dependently inhibited the proliferation of the HCC cell lines PLC/PRF/7, HuH7 and HepG2 with IC₅₀ values of 137, 108 and 140.7 μmol/L, respectively. No obvious expression of TRPV1 channel was detected in the 3 HCC cell lines and TRPV1 channel blockers did not alleviate the cytotoxicity of capsaicin. By contrast, combining capsaicin and sorafenib significantly enhanced the suppression on cell proliferation, achieving a high-level synergistic effect (inhibition rates over 50%) and promoting HCC cell apoptosis. In nude mice with PLC/PRF/5 xenografts, combined administration of capsaicin and sorafenib significantly enhanced the suppression on tumor growth without apparent gross toxicity compared to either agent alone. Mechanistically, capsaicin (10-200 μmol/L) dose-dependently increased the levels of phosphorylated ERK (p-ERK) in PLC/PRF/5 cells, thus leading to enhanced sorafenib sensitivity and a synergistic suppression on the tumor cells. Taken together, our results suggest that capsaicin-increased phosphorylation of ERK contributes to the enhanced antitumor activity of sorafenib, and capsaicin may be useful in improving the efficacy of sorafenib for the treatment of HCC.

中文翻译：

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辣椒素通过增加ERK信号传导增强索拉非尼在肝癌细胞和小鼠异种移植肿瘤中的抗肿瘤活性。

索拉非尼是酪氨酸蛋白激酶的一种小抑制剂，目前是用于治疗晚期肝细胞癌（HCC）的标准化疗药物。尽管索拉非尼提高了HCC患者的生存率，但其疗效并不是最佳的，需要进一步改善。辣椒素是辣椒属辣椒的主要活性成分，它不仅是TRPV1通道的激动剂，而且还具有抗肿瘤活性，并增强了癌细胞对细胞毒性药物的敏感性。在这项研究中，我们研究了索拉非尼和辣椒素联合对体外和异种移植肝癌HCC细胞的抗肿瘤作用。单独使用辣椒素进行剂量依赖性抑制IC ₅₀抑制HCC细胞株PLC / PRF / 7，HuH7和HepG2的增殖值分别为137、108和140.7μmol/ L。在3种HCC细胞系中均未检测到TRPV1通道的明显表达，TRPV1通道阻滞剂并没有减轻辣椒素的细胞毒性。相比之下，将辣椒素和索拉非尼联合使用可显着增强对细胞增殖的抑制作用，达到高水平的协同作用（抑制率超过50％）并促进HCC细胞凋亡。在具有PLC / PRF / 5异种移植物的裸鼠中，与单独使用这两种药物相比，辣椒素和索拉非尼的联合给药显着增强了对肿瘤生长的抑制作用，而没有明显的总毒性。从机理上讲，辣椒素（10-200μmol/ L）剂量依赖性地增加PLC / PRF / 5细胞中磷酸化ERK（p-ERK）的水平，从而导致索拉非尼敏感性增强和对肿瘤细胞的协同抑制作用。