Feng Xu-Qin, Rong Li-Wen, Wang Rui-Xue, Zheng Xue-Lian, Zhang Lei, Zhang Lin, Lin Yong, Wang Xia, Li Zhi-Ping
Department of Abdomen Oncology, Cancer Center of West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Laboratory of Molecular and Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) of Ministry of Education, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Oncol Lett. 2018 Jul;16(1):648-653. doi: 10.3892/ol.2018.8640. Epub 2018 May 4.
Sorafenib is a small-molecule multi-kinase inhibitor approved by FDA as an oral agent for the treatment of hepatocellular carcinoma (HCC) and renal cell carcinoma. However, unresponsiveness and acquired resistance are commonly observed, which hinder the clinical use of sorafenib. As combination therapy is a promising approach to improve its efficacy, we investigated if sorafenib and luteolin combination is effective in killing human HCC cells. Cell death was examined by lactate dehydrogenase (LDH) releasing assay. Apoptosis was detected by flow cytometric. The activation of apoptotic pathway and c-Jun N-terminal kinase (JNK) signaling pathway was measured by western blot. The results showed that sorafenib and luteolin combination synergistically induced cytotoxicity in HCC cells, which was accompanied by potentiation of apoptosis as demonstrated by increased apoptotic cell populations, caspase activation, and suppression of cell death by the pan-caspase inhibitor z-VAD-fmk. Furthermore, the combination of both agents enhanced expression of phosphorylated form of JNK, and the JNK inhibitor SP600125 effectively attenuated cell death induced by the combination treatment. Thus, sorafenib and luteolin combination synergistically kills HCC cells through JNK-mediated apoptosis, and luteolin may be an ideal candidate for increasing the activity of sorafenib in HCC therapy.
索拉非尼是一种小分子多激酶抑制剂，已被美国食品药品监督管理局（FDA）批准作为口服药物用于治疗肝细胞癌（HCC）和肾细胞癌。然而，无反应性和获得性耐药很常见，这阻碍了索拉非尼的临床应用。由于联合治疗是提高其疗效的一种有前景的方法，我们研究了索拉非尼和木犀草素联合使用是否能有效杀死人肝癌细胞。通过乳酸脱氢酶（LDH）释放试验检测细胞死亡情况。通过流式细胞术检测细胞凋亡。通过蛋白质印迹法检测凋亡途径和c-Jun氨基末端激酶（JNK）信号通路的激活情况。结果表明，索拉非尼和木犀草素联合使用可协同诱导肝癌细胞的细胞毒性，伴随着凋亡增强，表现为凋亡细胞群体增加、半胱天冬酶激活以及泛半胱天冬酶抑制剂z-VAD-fmk抑制细胞死亡。此外，两种药物联合使用增强了JNK磷酸化形式的表达，JNK抑制剂SP600125有效减弱了联合治疗诱导的细胞死亡。因此，索拉非尼和木犀草素联合使用通过JNK介导的凋亡协同杀死肝癌细胞，木犀草素可能是提高索拉非尼在肝癌治疗中活性的理想候选药物。
