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: Teng Yu, Chao Chen, Yang Sun, Hui Sun, Tian-Hang Li, Jin Meng, Xianhua Shi
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 464 Issue 1 Pg. 286-91 (Aug 14 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 26116776 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• ABT-737
• Adenine Nucleotide Translocator 1
• Antineoplastic Agents
• BCL2 protein, human
• Biphenyl Compounds
• Cyclophilin D
• Lactones
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Nitrophenols
• PPIF protein, mouse
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• Spiro Compounds
• Sulfonamides
• sanglifehrin A
• Bcl2 protein, mouse
• Cyclosporine
• Cyclophilins
• Curcumin

Topics

• Adenine Nucleotide Translocator 1 (antagonists & inhibitors, genetics, metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Biphenyl Compounds (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Curcumin (pharmacology)
• Cyclophilin D
• Cyclophilins (antagonists & inhibitors, genetics, metabolism)
• Cyclosporine (pharmacology)
• Drug Synergism
• Gene Expression Regulation, Neoplastic
• Humans
• Lactones (pharmacology)
• Melanoma, Experimental (genetics, metabolism, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mitochondria (drug effects, metabolism)
• Mitochondrial Membrane Transport Proteins (agonists, genetics, metabolism)
• Mitochondrial Permeability Transition Pore
• Nitrophenols (pharmacology)
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Signal Transduction
• Spiro Compounds (pharmacology)
• Sulfonamides (pharmacology)