title: ABT-737 sensitizes curcumin-induced anti-melanoma cell activity through facilitating mPTP death pathway.
abstract: In the current study, we studied the potential role of ABT-737, a novel Bcl-2 inhibitor, on curcumin-induced anti-melanoma cell activity in vitro. The associated mechanisms were also investigated. We demonstrated that ABT-737 significantly sensitized curcumin-induced activity against melanoma cells (WM-115 and B16 lines), resulting in substantial cell death and apoptosis with co-administration. At the molecular level, curcumin and ABT-737 synergistically induced mitochondrial permeability transition pore (mPTP) opening in melanoma cells, the latter was evidenced by mitochondrial membrane potential (MPP) reduction and mitochondrial complexation between cyclophilin-D (CyPD) and adenine nucleotide translocator 1 (ANT-1). Significantly, mPTP blockers, including cyclosporin A and sanglifehrin A, remarkably inhibited curcumin and ABT-737 co-administration-induced cytotoxicity against melanoma cells. Meanwhile, siRNA-mediated knockdown of CyPD or ANT-1, the two key components of mPTP, alleviated WM-116 cell death by the co-treatment. Collectively, we show that ABT-737 sensitizes curcumin-induced anti-melanoma cell activity probably through facilitating mPTP death pathway. ABT-737 could be further investigated as a potential curcumin adjuvant in melanoma and other cancer treatment.
authors.affiliation: Department of Dermatology, Shandong Ji-ning No.1 People's Hospital, Ji-ning City, Shandong Province, 272011, PR China. Electronic address: tengyu33@yahoo.com.
authors.forename: Teng
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Ophthalmology, Shandong Ji-ning No.1 People's Hospital, Ji-ning City, Shandong Province, 272011, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Thoracic Surgery, Shandong Ji-ning No.1 People's Hospital, Ji-ning City, Shandong Province, 272011, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Blood Transfusion, Shandong Ji-ning No.1 People's Hospital, Ji-ning City, Shandong Province, 272011, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Dermatology, Shandong Ji-ning No.1 People's Hospital, Ji-ning City, Shandong Province, 272011, PR China.
authors.forename: Tian-Hang
authors.initials: TH
authors.lastname: Li
authors.affiliation: Department of Dermatology, Shandong Ji-ning No.1 People's Hospital, Ji-ning City, Shandong Province, 272011, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Dermatology, Shandong Ji-ning No.1 People's Hospital, Ji-ning City, Shandong Province, 272011, PR China.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Shi
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013141:Spiro Compounds / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D033741:Adenine Nucleotide Translocator 1; D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D001713:Biphenyl Compounds; D000081406:Peptidyl-Prolyl Isomerase F; D007783:Lactones; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009596:Nitrophenols; C000631446:PPIF protein, mouse; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013141:Spiro Compounds; D013449:Sulfonamides; C121329:sanglifehrin A; C052617:Bcl2 protein, mouse; D016572:Cyclosporine; D021983:Cyclophilins; D003474:Curcumin
keywords: ABT-737; Cell death and chemo-sensitization; Curcumin; Melanoma; Mitochondrial permeability transition pore (mPTP)