Profiling flavonoid cytotoxicity in human breast cancer cell lines: Determination of structure-function relationships

Department of Biological Sciences, San Jose State University, San Jose, CA 95192, USA.
Natural product communications (Impact Factor: 0.91). 10/2012; 7(10):1295-304.
Source: PubMed


Flavonoids have been shown to be cytotoxic to cancer cells. However, the mechanism of cytotoxicity has not been clearly defined. It has previously been reported that HER2/ERBB2, the estrogen receptor, progesterone receptor, and p53 were required for flavonoid induced cytotoxicity in breast cancer cell lines. We have used a panel of breast cancer cell lines, known to contain as well as be deficient in these signaling pathways, to screen fourteen different flavonoids. Comparing the cytotoxicity for all flavonoids allows us to determine if a structure-functional relationship exists between cytotoxicity and flavonoid, and if a particular signaling pathway is required for cytotoxicity. We show that several flavonoids are cytotoxic to all cell lines including primary mammary epithelial cells tested. The cytotoxic flavonoids are also able to inhibit Mitochondrial Outer Membrane Permeability while at the same time stimulate ATP levels whereas the non-cytotoxic flavonoids are not able to do this. We also show that both cytotoxic and non-cytotoxic flavonoids can transverse the cell membrane to enter MDA-MB-231 cells at different levels. Finally, all flavonoids regardless of their cytotoxicity were able to induce some form of cell cycle arrest. We conclude that for flavonoids to be strongly cytotoxic, they must possess the 2,3-double bond in the C-ring and we believe the cytotoxicity occurs through mitochondrial poisoning in both cancer and normal cells.

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    • "Thus, these different classes of phytochemicals, by different mechanisms, are known to combat breast cancer. But several phytochemicals have been shown to have biphasic effect on cell survival, that is, they can aid inhibition as well as proliferation of breast cancer cells, depending on the concentration [36]. A major caveat for the effective action of phytochemicals is their bioavailability and distribution to tissues and organs which varies according to their category and might depend on molecular size, polarity, and solubility [37]. "
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