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.
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: DaoHai Zhang; Lee Kian Tai; Lee Lee Wong; Lily-Lily Chiu; Sunil K Sethi; Evelyn S C Koay Journal: Mol Cell Proteomics Date: 2005-07-26 Impact factor: 5.911
Authors: F Boccardo; A Rubagotti; P Guglielmini; A Fini; G Paladini; M Mesiti; M Rinaldini; S Scali; M Porpiglia; C Benedetto; N Restuccia; F Buzzi; R Franchi; B Massidda; V Distante; D Amadori; P Sismondi Journal: Ann Oncol Date: 2006-06 Impact factor: 32.976
Authors: Suman K Samanta; Anuradha Sehrawat; Su-Hyeong Kim; Eun-Ryeong Hahm; Yongli Shuai; Ruchi Roy; Subrata K Pore; Krishna B Singh; Susan M Christner; Jan H Beumer; Nancy E Davidson; Shivendra V Singh Journal: J Natl Cancer Inst Date: 2016-12-31 Impact factor: 13.506
Authors: Marie L Antony; Joomin Lee; Eun-Ryeong Hahm; Su-Hyeong Kim; Adam I Marcus; Vandana Kumari; Xinhua Ji; Zhen Yang; Courtney L Vowell; Peter Wipf; Guy T Uechi; Nathan A Yates; Guillermo Romero; Saumendra N Sarkar; Shivendra V Singh Journal: J Biol Chem Date: 2013-12-02 Impact factor: 5.157