Disease Subtype-Independent Biomarkers of Breast Cancer Chemoprevention by the Ayurvedic Medicine Phytochemical Withaferin A.

ABSTRACT: A nontoxic chemopreventive intervention efficacious against different subtypes of breast cancer is still a clinically unmet need. The present study was undertaken to determine the efficacy of an Ayurvedic medicine phytochemical (Withaferin A, [WA]) for chemoprevention of breast cancer and to elucidate its mode of action.Chemopreventive efficacy of WA (4 and 8?mg/kg body weight) was determined using a rat model of breast cancer induced by N-methyl-N-nitrosourea (MNU; n?=?14 for control group, n?=?15 for 4?mg/kg group, and n?=?18 for 8?mg/kg group). The mechanisms underlying breast cancer chemoprevention by WA were elucidated by immunoblotting, biochemical assays, immunohistochemistry, and cytokine profiling using plasma and tumors from the MNU-rat (n?=?8-12 for control group, n?=?7-11 for 4?mg/kg group, and n?=?8-12 for 8?mg/kg group) and/or mouse mammary tumor virus-neu (MMTV-neu) models (n?=?4-11 for control group and n?=?4-21 for 4?mg/kg group). Inhibitory effect of WA on exit from mitosis and leptin-induced oncogenic signaling was determined using MCF-7 and/or MDA-MB-231 cells. All statistical tests were two-sided.Incidence, multiplicity, and burden of breast cancer in rats were decreased by WA administration. For example, the tumor weight in the 8?mg/kg group was lower by about 68% compared with controls (8?mg/kg vs control, mean = 2.76 vs 8.59, difference = -5.83, 95% confidence interval of difference = -9.89 to -1.76, P = .004). Mitotic arrest and apoptosis induction were some common determinants of breast cancer chemoprevention by WA in the MNU-rat and MMTV-neu models. Cytokine profiling showed suppression of plasma leptin levels by WA in rats. WA inhibited leptin-induced oncogenic signaling in cultured breast cancer cells.WA is a promising chemopreventative phytochemical with the ability to inhibit at least two different subtypes of breast cancer.

SUBMITTER: Samanta SK 

PROVIDER: S-EPMC5928779 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature