title: Apoptosis induced by Ginkgo biloba (EGb761) in melanoma cells is Mcl-1-dependent.
abstract: 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.
authors: Department of Pathophysiology, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P.R. China.
authors: Yufang
authors: Y
authors: Wang
authors: Department of Pharmacology, Beijing Institute of Biomedicine, Beijing, P.R. China.
authors: Junping
authors: J
authors: Lv
authors: Department of Pathophysiology, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P.R. China.
authors: Yao
authors: Y
authors: Cheng
authors: Department of Pathophysiology, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P.R. China.
authors: Jipei
authors: J
authors: Du
authors: Department of Pathophysiology, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P.R. China.
authors: Degao
authors: D
authors: Chen
authors: Shanghai Key Laboratory of Forensic Medicine, Institute of Forensic Sciences, Ministry of Justice, Shanghai, P.R. China.
authors: Chengtao
authors: C
authors: Li
authors: Department of Forensic Genetics, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P.R. China.
authors: Ji
authors: J
authors: Zhang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D020441:Ginkgo biloba; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000096983:Ginkgo Extract
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020169:Caspases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C494772:BAK1 protein, human; C494826:BAX protein, human; C579095:MCL1 protein, human; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract