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Research ArticleArticle

Mitochondria, Calcium, and Calpain are Key Mediators of Resveratrol-Induced Apoptosis in Breast Cancer

Dhruv Sareen, Soesiawati R. Darjatmoko, Daniel M. Albert and Arthur S. Polans
Molecular Pharmacology December 2007, 72 (6) 1466-1475; DOI: https://doi.org/10.1124/mol.107.039040
Dhruv Sareen
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Soesiawati R. Darjatmoko
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Daniel M. Albert
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Arthur S. Polans
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Abstract

Resveratrol (RES), a natural plant polyphenol, has gained interest as a nontoxic 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 antiproliferative and induces apoptosis in a concentration- and time-dependent manner. Preceding apoptosis, RES instigates a rapid dissipation of mitochondrial membrane potential by directly targeting mitochondria. This is followed by release of cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) into the cytoplasm and substantial increase in the activities of caspases-9 and -3 in MDA-MB-231 cells. In addition, live cell microscopy demonstrates that RES causes an early biphasic increase in the concentration of free intracellular calcium ([Ca2+]i), probably resulting from depletion of the endoplasmic reticulum stores in breast cancer cells. In caspase-3–deficient MCF-7 cells, apoptosis is mediated by the Ca2+-activated protease, calpain, leading to the degradation of plasma membrane Ca2+-ATPase isoform 1 and fodrin; the degradation is attenuated by buffering [Ca2+]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. Together, these results suggest a critical role for mitochondria not only in the intrinsic apoptotic pathway but also in the Ca2+ and calpain-dependent cell death initiated by RES. Thus, RES may prove useful as a nontoxic alternative for breast cancer treatment.

Footnotes

  • This work was supported by National Institutes of Health grant R01-CA103653 (to A.S.P.) and grants from the Retina Research Foundation (to A.S.P.), the Mandelbaum Cancer Theraputics Initiative (to A.S.P. and D.M.A.), and National Institutes of Health core grant P30-EY016665-02.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.039040.

  • ABBREVIATIONS: RES, resveratrol; PMCA, plasma membrane Ca2+-ATPase; ER, endoplasmic reticulum; ΔΨm, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; DMSO, dimethyl sulfoxide; Smac/DIABLO, second mitochondria-derived activator of caspases/direct IAP binding protein with low pI; Ac-, N-acetyl-; AFC, amino-4-trifluoromethylcoumarin; AMC, amino-4-methylcoumarin; Z-, N-benzyloxycarbonyl-; ROI, region of interest; CsA, cyclosporin A; CICR, Ca2+-induced Ca2+ release; S-LLVY-AMC, succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin; JC-1, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-benzamidazolocarbocyanin iodide; FCCP, carbonyl cyanide-p-(trifluoromethoxy)phenylhydrazone; BAPTA-AM, 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-acetoxymethyl ester; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate; AM, acetoxymethyl ester; TG, thapsigargin; PD 150606, (2S)-3-(4-iodophenyl)-2-sulfanylpropanoic acid; SJA 6017, N-(4-fluorophenylsulfonyl)-l-valyl-l-leucinal; MDL 28170, N-benzyloxycarbonyl-Val-Phe-aldehyde.

    • Received June 13, 2007.
    • Accepted September 10, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (6)
Molecular Pharmacology
Vol. 72, Issue 6
1 Dec 2007
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Research ArticleArticle

Mitochondria, Calcium, and Calpain are Key Mediators of Resveratrol-Induced Apoptosis in Breast Cancer

Dhruv Sareen, Soesiawati R. Darjatmoko, Daniel M. Albert and Arthur S. Polans
Molecular Pharmacology December 1, 2007, 72 (6) 1466-1475; DOI: https://doi.org/10.1124/mol.107.039040

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Research ArticleArticle

Mitochondria, Calcium, and Calpain are Key Mediators of Resveratrol-Induced Apoptosis in Breast Cancer

Dhruv Sareen, Soesiawati R. Darjatmoko, Daniel M. Albert and Arthur S. Polans
Molecular Pharmacology December 1, 2007, 72 (6) 1466-1475; DOI: https://doi.org/10.1124/mol.107.039040
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