withaferin-a and Retroviridae-Infections

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.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetyl Coenzyme A; Aldehyde Dehydrogenase 1 Family; Animals; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Cell Cycle; Cytokines; Deoxyguanosine; Electron Transport Complex III; Female; Forkhead Transcription Factors; Humans; Ki-67 Antigen; Lactic Acid; Leptin; Malates; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; MCF-7 Cells; Methylnitrosourea; Mice; Mitosis; Mitotic Index; Rats; Receptors, Estrogen; Retinal Dehydrogenase; Retroviridae Infections; Signal Transduction; Tumor Burden; Tumor Virus Infections; Withanolides