Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany.
J Pineal Res. 2017 Apr;62(3). doi: 10.1111/jpi.12398. Epub 2017 Mar 6.
Melatonin has been shown to exert anticancer activity on hepatocellular carcinoma (HCC) through its antiproliferative and pro-apoptotic effect in both experimental and clinical studies, and sorafenib is the only approved drug for the systemic treatment of HCC. Thus, this study was designed to investigate the combined effect of melatonin and sorafenib on proliferation, apoptosis, and its possible mechanism in human HCC. Here, we found that both melatonin and sorafenib resulted in a dose-dependent growth inhibition of HuH-7 cells after 48 hours treatment, and the combination of them enhanced the growth inhibition in a synergistic manner. Colony formation assay indicated that co-treatment of HuH-7 cells with melatonin and sorafenib significantly decreased the clonogenicity compared to the treatment with single agent. Furthermore, FACS and TUNEL assay confirmed that melatonin synergistically augmented the sorafenib-induced apoptosis after 48 hours incubation, which was in accordance with the activation of caspase-3 and the JNK/c-jun pathway. Inhibition of JNK/c-jun pathway with its inhibitor SP600125 reversed the phosphorylation of c-jun and the activation of caspase-3 induced by co-treatment of HuH-7 cells with melatonin and sorafenib in a dose-dependent manner. Furthermore, SP600125 exhibited protective effect against apoptosis induced by the combination of melatonin and sorafenib. This study demonstrates that melatonin in combination with sorafenib synergistically inhibits proliferation and induces apoptosis in human HCC cells; therefore, supplementation of sorafenib with melatonin may serve as a potential therapeutic choice for advanced HCC.
褪黑素已被证明通过其在实验和临床研究中的抗增殖和促凋亡作用对肝细胞癌（HCC）具有抗癌活性，而索拉非尼是唯一被批准用于 HCC 全身治疗的药物。因此，本研究旨在研究褪黑素和索拉非尼联合对人 HCC 细胞增殖、凋亡的影响及其可能的机制。在这里，我们发现褪黑素和索拉非尼均可使 HuH-7 细胞在 48 小时处理后产生剂量依赖性的生长抑制，且两者联合具有协同作用。集落形成实验表明，与单独用药相比，HuH-7 细胞共处理褪黑素和索拉非尼可显著降低集落形成能力。此外，FACS 和 TUNEL 检测证实，与单独用药相比，褪黑素在 48 小时孵育后协同增强了索拉非尼诱导的细胞凋亡，这与 caspase-3 的激活和 JNK/c-jun 途径有关。用 JNK/c-jun 途径抑制剂 SP600125 抑制 JNK/c-jun 途径可逆转 HuH-7 细胞共处理褪黑素和索拉非尼诱导的 c-jun 磷酸化和 caspase-3 激活，且呈剂量依赖性。此外，SP600125 对褪黑素和索拉非尼联合诱导的细胞凋亡具有保护作用。本研究表明，褪黑素与索拉非尼联合可协同抑制人 HCC 细胞增殖并诱导细胞凋亡；因此，在索拉非尼治疗中补充褪黑素可能是晚期 HCC 的一种潜在治疗选择。
