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Molecules 2017, 22(3), 462; doi:10.3390/molecules22030462

Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin

1
Department of Obstetrics & Gynecology, University of California, Irvine, Orange, CA 92868, USA
2
Department of Urology, University of California, Irvine, Orange, CA 92868, USA
3
Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10476, USA
4
Department of Pharmacology, University of California, Irvine, Orange, CA 92868, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Santosh K. Katiyar
Received: 22 January 2017 / Revised: 8 March 2017 / Accepted: 10 March 2017 / Published: 14 March 2017
(This article belongs to the Special Issue Cancer Chemoprevention)
View Full-Text   |   Download PDF [1851 KB, uploaded 14 March 2017]   |  

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. View Full-Text
Keywords: Flavokawain A; HER2 overexpression; resistance to apoptosis Flavokawain A; HER2 overexpression; resistance to apoptosis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Jandial, D.D.; Krill, L.S.; Chen, L.; Wu, C.; Ke, Y.; Xie, J.; Hoang, B.H.; Zi, X. Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin. Molecules 2017, 22, 462.

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