Journal
LIFE SCIENCES
Volume 80, Issue 3, Pages 245-253Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2006.09.006
Keywords
intracellular calcium; apoptosis; calpain; caspase-12; MCF-7 cells; breast cancer; flavonoids; flavones; methoxyflavones; polymethoxyflavones; sweet orange (Citrus sinensis L.)
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Flavonoids, polyphenolic phytochemicals which include flavones and isoflavones, are present in the common human diet. It has been suggested that these compounds may exert anticancer activity; however, the mechanisms involved remain unknown. We have recently shown (Sergeev, 2004, Biochem Biophys Res Commun 321: 462-467) that isoflavones can activate the novel apoptotic pathway mediated by cellular Ca2+. Here, we report that polymethoxyflavones (PMFs) derived from sweet orange (Citrus sinensis L.) inhibit growth of human breast cancer cells via Ca2+-dependent apoptotic mechanism. The treatment of MCF-7 breast cancer cells with 5-hydroxy-3,6,7,8,3,4'-hexamethoxyflavone (5-OH-HxMF) and 3-hydroxy5,6,7,4'-tetramethoxyflavone (3'-OH-TtMF) induced a sustained increase in concentration of intracellular Ca2+ ([Ca2+](i)) resulting from both depletion of the endoplasmic reticulum Ca2+ stores and Ca2+ influx from the extracellular space. This increase in [Ca2+]i was associated with the activation of the Ca2+-dependent apoptotic proteases, It-calpain and caspase-12, as evaluated with the calpain and caspase-12 peptide substrates and antibodies to active (cleaved) forms of the enzymes. Corresponding non-hydroxylated PMFs, 3,5,6,7,8,3',4-heptamethoxyflavone (HpMF) and 5,6,7,3',4'pentamethoxyflavone (PtMF), were dramatically less active in inducing Ca2+-mediated apoptosis. Our results strongly suggest that the cellular Ca2+ modulating activity of flavonoids underlies their apoptotic mechanism and that hydroxylation of PMFs is critical for their ability to induce an increase in [Ca2+](i) and, thus, activate Ca2+-dependent apoptotic proteases. (c) 2006 Elsevier Inc. All rights reserved.
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