Decreased Expression of Stem Cell Markers by Simvastatin in 7,12-dimethylbenz(a)anthracene (DMBA)–induced Breast Cancer

• Published in: Toxicologic pathology Vol. 43; no. 3; pp. 400 - 410
• Main Authors: Rennó, André Lisboa, Alves-Júnior, Marcos José, Rocha, Rafael Malagoli, De Souza, Philipi Coutinho, de Souza, Valéria Barbosa, Jampietro, Juliano, Vassallo, José, Hyslop, Stephen, Anhê, Gabriel Forato, de Moraes Schenka, Natália Guimarães, Soares, Fernando Augusto, Schenka, André Almeida
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01-04-2015
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - toxicity; Animals; Antigens, CD - metabolism; Biomarkers; Biomarkers, Tumor - metabolism; Carcinogens - toxicity; Disease Progression; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Immunohistochemistry; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - metabolism; Necrosis; Neoplastic Stem Cells - metabolism; Rats; Rats, Sprague-Dawley; Simvastatin - pharmacology; simvastatin; DMBA; cancer stem cells; CD24; CD34; CD44; CD133
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623314544707

Simvastatin, a competitive inhibitor of HMG-CoA reductase widely used in the treatment and prevention of hyperlipidemia-related diseases, has recently been associated to in vitro anticancer stem cell (CSC) actions. However, these effects have not been confirmed in vivo. To assess in vivo anti-CSC effects of simvastatin, female Sprague-Dawley rats with 7,12-dimethyl-benz(a)anthracene (DMBA)–induced mammary cancer and control animals were treated for 14 days with either simvastatin (20 or 40 mg/kg/day) or soybean oil (N = 60). Tumors and normal breast tissues were removed for pathologic examination and immunodetection of CSC markers. At 40 mg/kg/day, simvastatin significantly reduced tumor growth and the expression of most CSC markers. The reduction in tumor growth (80%) could not be explained solely by the decrease in CSCs, since the latter accounted for less than 10% of the neoplasia (differentiated cancer cells were also affected). Stem cells in normal, nonneoplastic breast tissues were not affected by simvastatin. Simvastatin was also associated with a significant decrease in proliferative activity but no increase in cell death. In conclusion, this is the first study to confirm simvastatin anti-CSC actions in vivo, further demonstrating that this effect is specific for neoplastic cells, but not restricted to CSCs, and most likely due to inhibition of cell proliferation.