Abstract
HER2/neu positive breast tumors predict a high mortality and comprise 25%–30% of breast cancer. We have shown that Flavokawain A (FKA) preferentially reduces the viabilities of HER2-overexpressing breast cancer cell lines (i.e., SKBR3 and MCF7/HER2) versus those with less HER2 expression (i.e., MCF7 and MDA-MB-468). FKA at cytotoxic concentrations to breast cancer cell lines also has a minimal effect on the growth of non-malignant breast epithelial MCF10A cells. FKA induces G2M arrest in cell cycle progression of HER2-overexpressing breast cancer cell lines through inhibition of Cdc2 and Cdc25C phosphorylation and downregulation of expression of Myt1 and Wee1 leading to increased Cdc2 kinase activities. In addition, FKA induces apoptosis in SKBR3 cells by increasing the protein expression of Bim and BAX and decreasing expression of Bcl2, BclX/L, XIAP, and survivin. FKA also downregulates the protein expression of HER-2 and inhibits AKT phosphorylation. Herceptin plus FKA treatment leads to an enhanced growth inhibitory effect on HER-2 overexpressing breast cancer cell lines through downregulation of Myt1, Wee1, Skp2, survivin, and XIAP. Our results suggest FKA as a promising and novel apoptosis inducer and G2 blocking agent that, in combination with Herceptin, enhances for the treatment of HER2-overexpressing breast cancer.
Highlights
Conventional chemo-/radio-therapies for breast cancer non- cause deleterious effects to healthy tissues and have been associated with significant side effects, including cardiotoxicity [1,2].In this regard, some phytochemicals are either part of the human diet or consumed as dietary supplements and do not show adverse health effects even at large doses [3]
We have shown that Flavokawain A (FKA) preferentially inhibits the growth of Human epidermal-growth-factor receptor 2 (HER2)-overexpressing breast cancer cell lines versus those with less HER2 expression by downregulating the expression of Myt1 and Wee1 kinases leading to reduced phosphorylation levels of
SKBR3 was isolated from the pleural effusion of a 43-year-old female with metastatic ductal adenocarcinoma of the breast with HER2/neu amplification [23]
Summary
Conventional chemo-/radio-therapies for breast cancer non- cause deleterious effects to healthy tissues and have been associated with significant side effects, including cardiotoxicity [1,2]. In this regard, some phytochemicals are either part of the human diet or consumed as dietary supplements and do not show adverse health effects even at large doses [3]. We have shown that FKA preferentially inhibits the growth of HER2-overexpressing breast cancer cell lines versus those with less HER2 expression by downregulating the expression of Myt and Wee kinases leading to reduced phosphorylation levels of. FKA enhances the growth inhibitory effect of Herceptin on Her2-overexpressing breast cancer cells
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