Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway
Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway
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DOI：
10.1007/s13277-015-4526-4
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发表时间：
2016-05-01
期刊：
影响因子：
--
通讯作者：
Tsai, Jen-Pi
中科院分区：
文献类型：
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作者：
Lin, Ming-Te;Lin, Chia-Liang;Tsai, Jen-Pi
将抗肿瘤药物与生物活性化合物相结合是一种潜在的提高肿瘤细胞化疗效果的策略。本研究的目的是阐明黄酮类化合物非瑟酮联合多激酶抑制剂索拉非尼在体内外对人宫颈癌细胞的抗肿瘤作用。非瑟酮和索拉非尼联合应用可协同诱导HeLa细胞凋亡，同时线粒体膜电位损失显著增加。Caspase-3和Caspase-8的激活导致Bax/Bcl2比值升高，进而导致PARP水平的裂解，同时破坏线粒体膜电位，从而诱导HeLa细胞的凋亡。SiDR5处理的HeLa细胞Bax/Bc1-2比值降低，线粒体膜电位降低。此外，体内研究表明，在HeLa异种移植模型中，非瑟丁和索拉非尼联合治疗明显优于索拉非尼单独治疗。我们的研究表明，非瑟素和索拉非尼在体外和体内对人宫颈癌的协同作用比单独使用这两种药物都要好，这种协同作用是基于线粒体和DR5依赖的caspase-8/caspase-3信号通路的凋亡潜能。非塞汀和索拉非尼的联合治疗为晚期宫颈癌的进一步临床发展提供了一种新的治疗策略。
Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bc1-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.