Apoptosis induced by Ginkgo biloba (EGb761) in melanoma cells is Mcl-1-dependent.
Apoptosis induced by Ginkgo biloba (EGb761) in melanoma cells is Mcl-1-dependent.
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银杏叶 (EGb761) 在黑色素瘤细胞中诱导的细胞凋亡是 Mcl-1 依赖性的。
DOI：
10.1371/journal.pone.0124812
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Wang Y;Lv J;Cheng Y;Du J;Chen D;Li C;Zhang J
黑色素瘤是一种侵袭性皮肤癌。不幸的是，目前还没有化疗药物可以显著延长大多数转移性黑色素瘤患者的生存时间。在此，我们报道了银杏叶提取物(EGb761)，世界上销售最广泛的草药补充剂之一，通过扰乱促凋亡和抗凋亡的Bcl2家族蛋白之间的平衡，有效地诱导了人黑色素瘤细胞的凋亡。EGb761可诱导黑色素瘤细胞株发生不同程度的凋亡，但对黑素细胞无明显影响。细胞凋亡的诱导与线粒体膜电位的降低和Bax、Bak的激活有关，是caspase依赖的，可能是由线粒体途径介导的。尽管EGb761没有引起BH3-Only的BH3-Bcl2家族蛋白Bim、Puma、Noxa和Bad的表达水平的显著变化，但它显著下调了敏感但不耐药的黑色素瘤细胞中Mcl-1的表达，提示Mcl-1在调节EGb761诱导的黑色素瘤细胞凋亡中起主要作用。事实上，Mcl-1的siRNA敲除增强了EGb761诱导的细胞凋亡，这与Bax和Bak的激活有关。综上所述，这些结果表明，EGb761通过线粒体凋亡途径杀死黑色素瘤细胞，Mcl-1是黑色素瘤细胞对EGb761诱导的凋亡敏感性的主要调节因子。因此，EGb761联合靶向Mcl-1治疗黑色素瘤可能是一种有用的策略。
Melanoma is an aggressive skin cancer. Unfortunately, there is currently no chemotherapeutic agent available to significantly prolong the survival of the most patients with metastatic melanomas. Here we report that the Ginkgo biloba extract (EGb761), one of the most widely sold herbal supplements in the world, potently induces apoptosis in human melanoma cells by disturbing the balance between pro- and anti-apoptosis Bcl-2 family proteins. Treatment with EGb761 induced varying degrees of apoptosis in melanoma cell lines but not in melanocytes. Induction of apoptosis was caspase-dependent and appeared to be mediated by the mitochondrial pathway, in that it was associated with reduction in mitochondrial membrane potential and activation of Bax and Bak. Although EGb761 did not cause significant change in the expression levels of the BH3-only Bcl-2 family proteins Bim, Puma, Noxa, and Bad, it significantly downregulated Mcl-1 in sensitive but not resistant melanoma cells, suggesting a major role of Mcl-1 in regulating apoptosis of melanoma cells induced by EGb761. Indeed, siRNA knockdown of Mcl-1 enhanced EGb761-induced apoptosis, which was associated with increased activation of Bax and Bak. Taken together, these results demonstrate that EGb761 kills melanoma cells through the mitochondrial apoptotic pathway, and that Mcl-1 is a major regulator of sensitivity of melanoma cells to apoptosis induced by EGb761. Therefore, EGb761 with or without in combination with targeting Mcl-1 may be a useful strategy in the treatment of melanoma.
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