Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin.
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.
Department of Obstetrics & Gynecology, University of California, Irvine, Orange, CA 92868, USA. djandial@uci.edu.
Danielle D
DD
Jandial
Department of Obstetrics & Gynecology, University of California, Irvine, Orange, CA 92868, USA. lsmithkr@uci.edu.
Lauren S
LS
Krill
Department of Urology, University of California, Irvine, Orange, CA 92868, USA. syzyclx@163.com.
Lixia
L
Chen
Department of Urology, University of California, Irvine, Orange, CA 92868, USA. kedi2009@126.com.
Chunli
C
Wu
Department of Urology, University of California, Irvine, Orange, CA 92868, USA. ky@zzu.edu.cn.
Yu
Y
Ke
Department of Urology, University of California, Irvine, Orange, CA 92868, USA. xiej@uci.edu.
Jun
J
Xie
Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10476, USA. bahoang@montefiore.org.
Bang H
BH
Hoang
Department of Obstetrics & Gynecology, University of California, Irvine, Orange, CA 92868, USA. xzi@uci.edu.|Department of Urology, University of California, Irvine, Orange, CA 92868, USA. xzi@uci.edu.|Department of Pharmacology, University of California, Irvine, Orange, CA 92868, USA. xzi@uci.edu.
Xiaolin
X
Zi
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology*
D002599:Chalcone; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C500809:flavokawain A; C508053:ERBB2 protein, human
Flavokawain A; HER2 overexpression; resistance to apoptosis