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Lani · 09-13-2007, 10:59 PM

mitochondria, calcium metabolism

Mol Pharmacol. 2007 Sep 11; [Epub ahead of print]
Mitochondria, Calcium, and Calpain are Key Mediators of Resveratrol-Induced Apoptosis in Breast Cancer.

Sareen D, Darjatmoko SR, Albert DM, Polans AS.
University of Wisconsin - Madison.
Resveratrol (RES), a natural plant polyphenol, has gained interest as a non-toxic chemopreventive agent capable of inducing tumor cell death in a variety of cancer types. However, the early molecular mechanisms of RES-induced apoptosis are not well defined. Using the human breast cancer cell lines MDA-MB-231 and MCF-7, we demonstrate that RES is anti-proliferative and induces apoptosis in a concentration- and time-dependent manner. Preceding apoptosis, RES instigates a rapid dissipation of mitochondrial membrane potential (DeltaPsim) by directly targeting mitochondria. This is followed by release of cytochrome c and Smac/DIABLO into the cytoplasm and substantial increase in the activities of caspases-9 and -3 in MDA-MB-231 cells. Additionally, live cell microscopy demonstrates that RES causes an early biphasic increase in the concentration of free intracellular calcium ([Ca(2+)]i), likely resulting from depletion of the endoplasmic reticulum (ER) stores in breast cancer cells. In caspase-3 deficient MCF-7 cells apoptosis is mediated by the Ca(2+)- activated protease, calpain, leading to the degradation of plasma membrane Ca(2+)-ATPase isoform 1 (PMCA1) and fodrin; the degradation is attenuated by buffering [Ca(2+)]i and blocked by calpain inhibitors. Mitochondrial permeability transition pore antagonists also blocked calpain activation. In vivo mouse xenograft studies demonstrate that RES treatment inhibits breast cancer growth with no systemic toxicities. Collectively, these results suggest a critical role for mitochondria not only in the intrinsic apoptotic pathway but also in the Ca(2+) and calpain-dependent cell death initiated by RES. Thus, RES may prove useful as a non-toxic alternative for breast cancer treatment.
PMID: 17848600 [PubMed - as supplied by publisher]

09-13-2007, 10:59 PM	#1
Lani Senior Member Join Date: Mar 2006 Posts: 4,783	resveratrol (in wine, grape juice, etc) causes breast cancer cell death via effect on mitochondria, calcium metabolism Mol Pharmacol. 2007 Sep 11; [Epub ahead of print] Mitochondria, Calcium, and Calpain are Key Mediators of Resveratrol-Induced Apoptosis in Breast Cancer. Sareen D, Darjatmoko SR, Albert DM, Polans AS. University of Wisconsin - Madison. Resveratrol (RES), a natural plant polyphenol, has gained interest as a non-toxic chemopreventive agent capable of inducing tumor cell death in a variety of cancer types. However, the early molecular mechanisms of RES-induced apoptosis are not well defined. Using the human breast cancer cell lines MDA-MB-231 and MCF-7, we demonstrate that RES is anti-proliferative and induces apoptosis in a concentration- and time-dependent manner. Preceding apoptosis, RES instigates a rapid dissipation of mitochondrial membrane potential (DeltaPsim) by directly targeting mitochondria. This is followed by release of cytochrome c and Smac/DIABLO into the cytoplasm and substantial increase in the activities of caspases-9 and -3 in MDA-MB-231 cells. Additionally, live cell microscopy demonstrates that RES causes an early biphasic increase in the concentration of free intracellular calcium ([Ca(2+)]i), likely resulting from depletion of the endoplasmic reticulum (ER) stores in breast cancer cells. In caspase-3 deficient MCF-7 cells apoptosis is mediated by the Ca(2+)- activated protease, calpain, leading to the degradation of plasma membrane Ca(2+)-ATPase isoform 1 (PMCA1) and fodrin; the degradation is attenuated by buffering [Ca(2+)]i and blocked by calpain inhibitors. Mitochondrial permeability transition pore antagonists also blocked calpain activation. In vivo mouse xenograft studies demonstrate that RES treatment inhibits breast cancer growth with no systemic toxicities. Collectively, these results suggest a critical role for mitochondria not only in the intrinsic apoptotic pathway but also in the Ca(2+) and calpain-dependent cell death initiated by RES. Thus, RES may prove useful as a non-toxic alternative for breast cancer treatment. PMID: 17848600 [PubMed - as supplied by publisher]