Title: RESVERATROL-INDUCED APOPTOSIS IS ENHANCED IN ACUTE LYMPHOBLASTIC LEUKEMIA CELLS BY MODULATION OF THE MITOCHONDRIAL PERMEABILITY TRANSITION PORE Authors
Submitted to: Cancer Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: September 1, 2005
Publication Date: August 18, 2006
Citation: Zunino, S.J., Storms, D.H. 2006. RESVERATROL-INDUCED APOPTOSIS IS ENHANCED IN ACUTE LYMPHOBLASTIC LEUKEMIA CELLS BY MODULATION OF THE MITOCHONDRIAL PERMEABILITY TRANSITION PORE. Cancer Letters. Vol. 240:123-134. Interpretive Summary: Resveratrol, found in grapes and red wine, is an antioxidant that displays anti-cancer properties in a variety of cancer models. We have recently shown in the laboratory that resveratrol can kill different types of leukemia cells, including high-risk infant leukemia cells. These leukemia cells were used to understand how resveratrol can kill cancer cells by disrupting the energy state of the mitochondria, the organelle responsible for generation of energy for each cell. The mitochondria has a pore called the mitochondrial permeability transition pore in the membrane that opens and closes to allow small molecules to move in and out. Two chemicals that block the opening of this pore, cyclosporin A and bongkrekic acid, and one chemical that enhances the opening of the pore, PK11195, were used to study the role of this pore in resveratrol-induced death of the leukemia cells. We found that pretreating the leukemia cells with these chemicals significantly disrupted the energy status of the mitochondria and increased the ability of resveratrol to kill the leukemic cells. These results show that the mitochondrial pore is important in determining death and survival of the leukemia cells and interfering with its activity sensitizes the leukemia cells to killing by resveratrol.
Technical Abstract: We have recently shown that resveratrol (3,5,4'-trihydroxy-trans-stilbene), an antioxidant found at high concentrations in grapes and red wine, can induce apoptotic cell death in acute lymphoblastic leukemia (ALL)-derived cells, including high-risk, therapy-resistant B-lineage ALL containing the chromosomal translocation t(4;11). Apoptosis was induced in these cells via a mitochondria/caspase-9 specific pathway. The mitochondrial permeability transition pore (MPTP) located in the mitochondrial membrane has been proposed to play a critical role in regulating survival and death. Cyclosporin A and bongkrekic acid, which block the opening of the MPTP, and PK11195, which enhances pore opening, were used in conjunction with resveratrol to determine the role of the MPTP in resveratrol-induced apoptosis in B and T-lineage leukemic cells. We found that both inhibition and enhancement of pore opening significantly increased resveratrol-mediated apoptosis and loss of mitochondrial membrane potential, as measured by Annexin V staining and the mitochondria-selective dye JC-1, respectively. Since nitric oxide is involved in regulating mitochondrial membrane status, cells were also stained with the nitric oxide binding dye diaminofluorescein-FM diacetate. A 3- to 10-fold increase in nitric oxide levels was observed in these cells after exposure to the MPTP modulators plus resveratrol compared with the resveratrol only treatment group. These data suggest that modulation of the function of the MPTP may be useful for sensitizing these leukemic cells to the the anti-cancer activity of resveratrol.