Metabolic alterations in mammary cancer prevention by withaferin A in a clinically relevant mouse model.

Abstract

BACKGROUND:

Efficacy of withaferin A (WA), an Ayurvedic medicine constituent, for prevention of mammary cancer and its associated mechanisms were investigated using mouse mammary tumor virus-neu (MMTV-neu) transgenic model.

METHODS:

Incidence and burden of mammary cancer and pulmonary metastasis were scored in female MMTV-neu mice after 28 weeks of intraperitoneal administration with 100 µg WA (three times/week) (n = 32) or vehicle (n = 29). Mechanisms underlying mammary cancer prevention by WA were investigated by determination of tumor cell proliferation, apoptosis, metabolomics, and proteomics using plasma and/or tumor tissues. Spectrophotometric assays were performed to determine activities of complex III and complex IV. All statistical tests were two-sided.

RESULTS:

WA administration resulted in a statistically significant decrease in macroscopic mammary tumor size, microscopic mammary tumor area, and the incidence of pulmonary metastasis. For example, the mean area of invasive cancer was lower by 95.14% in the WA treatment group compared with the control group (mean = 3.10 vs 63.77 mm2, respectively; difference = -60.67 mm2; 95% confidence interval = -122.50 to 1.13 mm2; P = .0536). Mammary cancer prevention by WA treatment was associated with increased apoptosis, inhibition of complex III activity, and reduced levels of glycolysis intermediates. Proteomics confirmed downregulation of many glycolysis-related proteins in the tumor of WA-treated mice compared with control, including M2-type pyruvate kinase, phospho glycerate kinase, and fructose-bisphosphate aldolase A isoform 2.

CONCLUSIONS:

This study reveals suppression of glycolysis in WA-mediated mammary cancer prevention in a clinically relevant mouse model.

• Authors: Eun-Ryeong Hahm, Joomin Lee, Su-Hyeong Kim, Anuradha Sehrawat, Julie A Arlotti, Sruti S Shiva, Rohit Bhargava, Shivendra V Singh
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 105 Issue 15 Pg. 1111-22 (Aug 07 2013) ISSN: 1460-2105 [Electronic] United States
• PMID: 23821767 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Withanolides
• withaferin A

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cluster Analysis
• Electrophoresis, Gel, Two-Dimensional
• Female
• Glycolysis (drug effects)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Lung Neoplasms (prevention & control, secondary)
• Mammary Neoplasms, Experimental (metabolism, prevention & control, virology)
• Mammary Tumor Virus, Mouse
• Medicine, Ayurvedic
• Mice
• Mice, Transgenic
• Random Allocation
• Withanolides (pharmacology)