Flavokawain A inhibits the anchorage-dependent and independent growth of breast cancer cell lines and causes G2M arrest via down-regulation of Cdc2 inhibitors: Myt1 and Wee1. Free

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Flavokawain A is a predominant chalcone isolated from Kava extracts. We have demonstrated that flaovkawain A preferentially inhibits cell proliferation of breast cancer cell lines MCF-7 and SKBR-3 with IC_50s of 16 and 4μM, respectively. In contrast, flavokawain A treatment with a concentration of up to 40 μM did not caused any significant inhibition on the cell growth of the normal breast epithelial cell line MCF10. Further studies showed that flavokawain A is more effective inhibiting colony formation of MCF-7/Her-2 (a cell line overexpressing Her-2 receptor) in soft agar than the parental MCF-7 cell line. FACS analysis revealed that flavokawain A induced G2M arrest in cell cycle progression of these breast cancer cell lines. While overexpression of Her-2 in breast cancer has been reported to cause tyrosine-15 hyperphosphorylation of Cdc2 (an inactive form of Cdc2), we demonstrated that flavokawain A treatment of breast cancer cell lines resulted in a significant decrease in Cdc2 inhibitors: Myt1 and Wee1 in a time and dose-dependent manner. Additionally, flavoakwain A increased PARP cleavage, down-regulated XIAP and induced BAX protein expression in breast cancer cells, suggestive of apoptosis induction. Together, our results support that flavokawain A down-regulates Cdc2 inhibitors: Myt1 and Wee1 which subsequently increases Cdc2 kinase activity, leading to premature mitosis, apoptosis and cell growth inhibition. Agents targeting Cdc2 activation may therefore be useful for treatment of Her-2 overexpressing breast tumors.