Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

Abstract

Epidemiological studies indicate that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, play a role in inhibition of several human neoplasia including breast cancer. In this study, chemopreventive effects of atorvastatin in N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. Atorvastatin was administered in the diet at two concentrations: 10 mg/kg (ATOR 10) and 100 mg/kg (ATOR 100). Atorvastatin treatment began 8 days prior to carcinogen administration and subsequently continued for 15 weeks till the end of the experiment. Atorvastatin at a higher dose suppressed tumor frequency by 80.5% (P = 0.0008) and tumor incidence by 49.5% (P = 0.015), and extended latency period by 14 days (P = 0.076) when compared to the control group. Atorvastatin at a lower dose did not significantly alter tumor parameters in comparison with the control group. In the specimens of mammary tumors, atorvastatin (in the ATOR 100 group) significantly decreased mRNA expression of Bcl-2 gene but non-significantly increased Bax mRNA expression compared to control group. Atorvastatin administration did not alter serum concentration of triacylglycerols, total cholesterol, and LDL cholesterol in comparison with controls. This study is the first report on tumor suppressive effect of atorvastatin in rat mammary carcinogenesis.

Immunohistochemical and histomorphological analysis of rat mammary tumors after simvastatin treatment

“…On the other hand, the lower concentration of simvastatin -18 mg/kg in our experiment (equivalent to daily clinical doses) was ineffective in animals. Similarly, significant antitumor effects of atorvastatin (100 mg/kg of diet) administered in the chemoprevention of NMU-induced rat mammary carcinogenesis in our previous study were observed [9]. In our last experiment, hydrophilic rosuvastatin (250 mg/kg of diet) has shown lower chemopreventive activity than lipophilic statins in this model of experimental breast cancer [13].…”

“…After fluvastatin treatment, expression of Bcl-2 and procaspase-9 were downregulated, cytochrome c (cytosolic extract), Bax and cleaved-caspase-3 protein expression increased [8]. In this context, pro-apoptotic shift of ratio in Bax/Bcl-2 mRNA expression in rat mammary tumor cells caused by atorvastatin in our previous experiment was confirmed [9].…”

Melatonin potentiates the anti‐tumour effect of pravastatin in rat mammary gland carcinoma model

“…Proposed mechanisms for statin-mediated apoptosis include an upregulation of pro-apoptotic protein expression (Bax, Bim) together with decreased anti-apoptotic protein expression (Bcl-2) (Yu et al 2013), or activation of caspase-3, caspase-7, caspase-8 and caspase-9 (Cafforio et al 2005). In our previous experiments there was a pro-apoptotic shift in Bax/Bcl-2 mRNA expression in rat mammary tumour cells after atorvastatin treatment (Kubatka et al 2011a) and pro-apoptotic shift in Bcl-2/Bax protein expression after simvastatin treatment were observed. However, our recent results did not suggest clear pro-apoptotic effects of fluvastatin in rat mammary carcinomas (Kubatka et al 2013).…”

“…On the other hand, significant anti‐tumour effects of dietary administered lipophilic statins (atorvastatin, simvastatin and fluvastatin) in the chemoprevention of rat mammary carcinogenesis in our previous studies were observed (Kubatka et al . , , ). In our recent experiment, hydrophilic rosuvastatin (250 mg/kg) has shown lower non‐significant anti‐neoplastic activity than lipophilic statins in this model of experimental breast cancer (Kubatka et al .…”

“…In our previous experiments there was a pro‐apoptotic shift in Bax/Bcl‐2 mRNA expression in rat mammary tumour cells after atorvastatin treatment (Kubatka et al . ) and pro‐apoptotic shift in Bcl‐2/Bax protein expression after simvastatin treatment (Kubatka et al . ) were observed.…”