In Vivo Anti-Tumoral Effects of Simvastatin in a Cancer Stem Cell-Rich Model of Breast Carcinoma
Andre L Renno, Philipi C De Souza, Valeria B De Souza, Cristielle P Freitas, Marina Pavanello, Gilberto C Franchi, Jr, Alexandre E Nowill, Natalia GM Schenka, Rafael M Rocha, Glauce A Pinto, Fernando A Soares, Jose Vassallo, Laura F Rezende, Andre A Schenka. UNICAMP, Campinas, SP, Brazil; Hospital do Cancer A. C. Camargo, Sao Paulo, Brazil; UNIFAE, Sao Joao Da Boa Vista, SP, Brazil
Background: Breast cancer is the most frequent malignant neoplasm and the leading cause of death from malignancy among women worldwide. Dimetil-benz(a)anthracene (DMBA) is of the most frequently used carcinogenic substances in the literature, being highly efficient and specific for breast carcinoma induction. Preliminary data from our group indicate that DMBA induced neoplasia is highly enriched in cancer stem cells (CSC), one of the major targets of current drug development research. Simvastatin is a competitive inhibitor of 3-hydroxy-3-methylgluraryl coenzyme A redutase (HMG-CoA), widely used in primary and secondary prevention of hyperlipidemic-related cardiovascular diseases. Simvastatin has recently been associated to in vitro anti-proliferation actions across a wide variety of malignant cell lines. Aim: this is the first study to report the antineoplastic effects of simvastatin on a DMBA-induced cancer stem cell-rich model of breast carcinoma.
Design: Mammary tumor induction was performed by single gavage administration of DMBA (100mg/kg) in virgin female Sprague-Dawely. When the tumors reached approximately 1cm3, the animals were treated for 14 days with simvastatin (40mg/kg/day in 1mL of soy oil, by gavage– Experimental Group, n=6) or with 1mL of soy (Control Group, n=6). After this 14-day protocol, the animals were euthanized and the tumors removed for macroscopic examination, volume measurement, histologic assessment and immunodetection of CSC markers (CD133 and Oct4).
Results: The average tumor size of simvastatin treated animals (0.88±1.05cm3) was significantly (p<0.05) smaller than that of control rats (2.39±0.69 cm3). However, at this point, CD133 and Oct4 immunoexpressions were not significantly affected by the treatment with simvastatin. Specific modifications in the immunohistochemical techniques (with the inclusion of alternative antibody clones and additional markers) and in the quantitation protocols are under scrutiny in order to confirm the latter findings.
Conclusions: These results indicate that simvastatin is effective in vivo as an antineoplastic agent in a model of breast carcinogenesis that favors the proliferation of cancer stem cells. Ongoing research in our laboratory is now focused on determining whether this antineoplastic action involves growth inhibition of cancer stem cells, more differentiated/committed neoplastic cells or both.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 280, Wednesday Morning