Abstract |
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 Ca(2+). Here, we report that polymethoxyflavones (PMFs) derived from sweet orange (Citrus sinensis L.) inhibit growth of human breast cancer cells via Ca(2+)-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'-hydroxy-5,6,7,4'-tetramethoxyflavone (3'-OH-TtMF) induced a sustained increase in concentration of intracellular Ca(2+) ([Ca(2+)](i)) resulting from both depletion of the endoplasmic reticulum Ca(2+) stores and Ca(2+) influx from the extracellular space. This increase in [Ca(2+)](i) was associated with the activation of the Ca(2+)-dependent apoptotic proteases, mu-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 Ca(2+)-mediated apoptosis. Our results strongly suggest that the cellular Ca(2+) modulating activity of flavonoids underlies their apoptotic mechanism and that hydroxylation of PMFs is critical for their ability to induce an increase in [Ca(2+)](i) and, thus, activate Ca(2+)-dependent apoptotic proteases.
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Authors | Igor N Sergeev, Shiming Li, Julie Colby, Chi-Tang Ho, Slavik Dushenkov |
Journal | Life sciences
(Life Sci)
Vol. 80
Issue 3
Pg. 245-53
(Dec 23 2006)
ISSN: 0024-3205 [Print] Netherlands |
PMID | 17046027
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Isoflavones
- Calpain
- Caspase 12
- Calcium
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Topics |
- Apoptosis
(drug effects)
- Breast Neoplasms
(drug therapy, metabolism, pathology)
- Calcium
(metabolism)
- Calcium Signaling
(drug effects)
- Calpain
(metabolism)
- Caspase 12
(metabolism)
- Cell Line, Tumor
- Citrus sinensis
(chemistry)
- Endoplasmic Reticulum
(metabolism, pathology)
- Enzyme Activation
(drug effects)
- Female
- Humans
- Isoflavones
(chemistry, pharmacology, therapeutic use)
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