Resveratrol-induced apoptosis is enhanced in acute lymphoblastic leukemia cells by modulation of the mitochondrial permeability transition pore.
We have previously shown that resveratrol can induce apoptotic cell death in cell lines established from patients with acute lymphoblastic leukemia (ALL). Cyclosporin A (CsA) and PK11195 are modulators of the mitochondrial permeability transition pore (MPTP) which has been proposed to play a critical role in regulating survival and death. Using SEM and RS4;11 lines with the t(4;11) translocation, the B-ALL line REH, and the T-ALL line Jurkat, we show that pre-treatment with CsA or PK11195 significantly enhances resveratrol-mediated apoptosis and mitochondrial membrane depolarization in these cells, as measured by annexin V and JC-1 staining, respectively. No significant multi-drug resistance efflux of the fluorescent substrate calcein was observed in these ALL lines, indicating that CsA and PK11195 were acting at the level of the mitochondria to enhance loss of mitochondrial membrane potential and induction of apoptosis. These data suggest targeting the MPTP sensitizes B- and T-cell ALL to the anti-cancer activity of resveratrol, and may be particularly useful for the treatment of high-risk t(4;11) ALL.
Zunino
Susan J
SJ
United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, One Shields Ave., 3202A Meyer Hall, University of California, Davis, CA 95616, USA. szunino@whnrc.usda.gov <szunino@whnrc.usda.gov>
Storms
David H
DH
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002478:Cells, Cultured; D016572:Cyclosporine; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007546:Isoquinolines; D019169:Jurkat Cells; D008564:Membrane Potentials; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D007546:Isoquinolines; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013267:Stilbenes; D016572:Cyclosporine; D000077185:Resveratrol; C037850:PK 11195