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.
Keywords:
ABT-737; Cell death and chemo-sensitization; Curcumin; Melanoma; Mitochondrial permeability transition pore (mPTP).
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine Nucleotide Translocator 1 / antagonists & inhibitors
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Adenine Nucleotide Translocator 1 / genetics
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Adenine Nucleotide Translocator 1 / metabolism
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Animals
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Antineoplastic Agents / pharmacology*
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Biphenyl Compounds / pharmacology*
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Cell Death / drug effects
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Cell Line, Tumor
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Curcumin / pharmacology*
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Cyclophilins / antagonists & inhibitors
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Cyclophilins / genetics
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Cyclophilins / metabolism
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Cyclosporine / pharmacology
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Drug Synergism
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Gene Expression Regulation, Neoplastic*
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Humans
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Lactones / pharmacology
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Melanoma, Experimental / genetics
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Melanoma, Experimental / metabolism
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Melanoma, Experimental / pathology
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Membrane Potential, Mitochondrial / drug effects
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Mice
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Mitochondrial Membrane Transport Proteins / agonists*
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Mitochondrial Membrane Transport Proteins / genetics
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Mitochondrial Membrane Transport Proteins / metabolism
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Mitochondrial Permeability Transition Pore
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Nitrophenols / pharmacology*
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Peptidyl-Prolyl Isomerase F
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Piperazines / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Spiro Compounds / pharmacology
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Sulfonamides / pharmacology*
Substances
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ABT-737
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Adenine Nucleotide Translocator 1
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Antineoplastic Agents
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BCL2 protein, human
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Biphenyl Compounds
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Peptidyl-Prolyl Isomerase F
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Lactones
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Permeability Transition Pore
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Nitrophenols
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PPIF protein, mouse
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Spiro Compounds
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Sulfonamides
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sanglifehrin A
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Bcl2 protein, mouse
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Cyclosporine
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Cyclophilins
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Curcumin