Ayurvedic Medicine Constituent Withaferin A Causes G2 and M Phase Cell Cycle Arrest in Human Breast Cancer Cells
Authors
Silvia Stan
Department of Pharmacology & Chemical Biology, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Yan Zeng
Department of Pharmacology & Chemical Biology, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Shivendra Singh
Department of Pharmacology & Chemical Biology, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Keywords:
Withaferin A, Dietary Supplement, Breast Cancer, Cdc25C, Cell Cycle
Abstract
Withaferin A (WA) is derived from the medicinal plant Withania somnifera that has been safely used for centuries in the Indian Ayurvedic medicine for treatment of various ailments. We now demonstrate that WA treatment causes G2 and mitotic arrest in human breast cancer cells. Treatment of MDA-MB-231 (estrogen-independent) and MCF-7 (estrogen-responsive) cell lines with WA resulted in a concentration- and time-dependent increase in G2-M fraction, which correlated with a decrease in levels of cyclin-dependent kinase 1 (Cdk1), cell division cycle 25B (Cdc25B) and/or Cdc25C proteins leading to accumulation of Tyr15 phosphorylated (inactive) Cdk1. Ectopic expression of Cdc25C conferred partial yet significant protection against WA-mediated G2-M phase cell cycle arrest in MDA-MB-231 cells. The WA-treated MDA-MB-231 and MCF-7 cells were also arrested in mitosis as judged by fluorescence microscopy and analysis of Ser10 phosphorylated histone H3. Mitotic arrest resulting from exposure to WA was accompanied by an increase in the protein level of anaphase promoting complex/cyclosome substrate securin. In conclusion, the results of the present study suggest that G2-M phase cell cycle arrest may be an important mechanism in anti-proliferative effect of WA against human breast cancer cells.
Keywords: Withaferin A, Dietary Supplement, Breast Cancer, Cdc25C, Cell Cycle
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