title: Decreased expression of stem cell markers by simvastatin in 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, State University of Campinas (Unicamp), São Paulo, Brazil.
authors.forename: André Lisboa
authors.initials: AL
authors.lastname: Rennó
authors.affiliation: Department of Pharmacology, School of Medical Sciences, State University of Campinas (Unicamp), São Paulo, Brazil.
authors.forename: Marcos José
authors.initials: MJ
authors.lastname: Alves-Júnior
authors.affiliation: Laboratory of Investigative Pathology, Department of Anatomic Pathology, Hospital AC Camargo, São Paulo, Brazil.
authors.forename: Rafael Malagoli
authors.initials: RM
authors.lastname: Rocha
authors.affiliation: Department of Pharmacology, School of Medical Sciences, State University of Campinas (Unicamp), São Paulo, Brazil.
authors.forename: Philipi Coutinho
authors.initials: PC
authors.lastname: De Souza
authors.affiliation: Department of Pharmacology, School of Medical Sciences, State University of Campinas (Unicamp), São Paulo, Brazil.
authors.forename: Valéria Barbosa
authors.initials: VB
authors.lastname: de Souza
authors.affiliation: Laboratory of Investigative Pathology, Department of Anatomic Pathology, Hospital AC Camargo, São Paulo, Brazil.
authors.forename: Juliano
authors.initials: J
authors.lastname: Jampietro
authors.affiliation: Laboratory of Investigative Pathology, Department of Anatomic Pathology, Hospital AC Camargo, São Paulo, Brazil Laboratory of Investigative and Molecular Pathology, Center for Investigation in Pediatrics (Ciped), São Paulo, Brazil.
authors.forename: José
authors.initials: J
authors.lastname: Vassallo
authors.affiliation: Department of Pharmacology, School of Medical Sciences, State University of Campinas (Unicamp), São Paulo, Brazil.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hyslop
authors.affiliation: Department of Pharmacology, School of Medical Sciences, State University of Campinas (Unicamp), São Paulo, Brazil.
authors.forename: Gabriel Forato
authors.initials: GF
authors.lastname: Anhê
authors.affiliation: Laboratory of Investigative Pathology, Department of Anatomic Pathology, Hospital AC Camargo, São Paulo, Brazil.
authors.forename: Natália Guimarães
authors.initials: NG
authors.lastname: de Moraes Schenka
authors.affiliation: Laboratory of Investigative Pathology, Department of Anatomic Pathology, Hospital AC Camargo, São Paulo, Brazil.
authors.forename: Fernando Augusto
authors.initials: FA
authors.lastname: Soares
authors.affiliation: Department of Pharmacology, School of Medical Sciences, State University of Campinas (Unicamp), São Paulo, Brazil Laboratory of Investigative Pathology, Department of Anatomic Pathology, Hospital AC Camargo, São Paulo, Brazil Laboratory of Investigative and Molecular Pathology, Center for Investigation in Pediatrics (Ciped), São Paulo, Brazil schenka@hotmail.com schenka@fcm.unicamp.br.
authors.forename: André Almeida
authors.initials: AA
authors.lastname: Schenka
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity*; D018450:Disease Progression; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism*; D009336:Necrosis; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D014408:Biomarkers, Tumor; D002273:Carcinogens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015127:9,10-Dimethyl-1,2-benzanthracene; D019821:Simvastatin
keywords: CD133; CD24; CD34; CD44; DMBA.; cancer stem cells; simvastatin