Preventive effects of fluvastatin in rat mammary carcinogenesis

Abstract

On the basis of preclinical and clinical evidence, statins lead to risk reduction of several types of neoplasia including breast cancer. This study is the first report on the preventive effects of fluvastatin in experimental breast cancer in vivo. In this experiment, the antineoplastic effects of fluvastatin in the chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. The effects of fluvastatin on selected parameters of apoptosis, proliferation, and angiogenesis in mammary tumor cells were determined. The drug was dietary administered at two concentrations of 20 and 200 mg/kg. The experiment was terminated 17 weeks after carcinogen administration; mammary tumors were removed and prepared for histomorphological and immunohistochemical analysis. The basic parameters of experimental carcinogenesis, chosen metabolic variables, and side effects after long-term fluvastatin treatment in animals were assessed. Fluvastatin at higher concentrations suppressed tumor frequency by 63% and tumor incidence by 33% in comparison with the controls. After fluvastatin treatment, immunohistochemical analysis of tumor cells showed a decrease in vascular endothelial growth factor receptor-2 expression by 86% and an increase in caspase-3 by 8.5%. Fluvastatin in both treated groups significantly increased the parameters of serum lipid metabolism and significantly decreased femur compact bone thickness and body weight in animals. Our results suggest that fluvastatin and other statins should be further evaluated for tumor-preventive characteristics.

Association Between Statin Use and Endometrial Cancer Survival

“…Murine models of breast cancer when treated with statins were found to undergo increased apoptosis as well as decreased tumor cell proliferation. [10][11][12] Statins also reduced the proliferation of cancer cells in murine models of colon, liver, pancreatic, ovarian, and prostate cancers. [13][14][15][16] Epidemiologic studies have shown an inverse association of statin use with the incidence of uterine and ovarian cancer.…”

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

“…In our previous study, highly effective treatment of rat mammary carcinomas by fluvastatin caused only slight increase in caspase‐3 expression (Kubatka et al . ). In this experiment, the apoptosis execution proteins caspase‐3 and caspase‐7 were significantly increased by pravastatin in tumour cells; moreover, with pravastatin+melatonin combination, this effect on both caspases noticeably enhanced.…”

“…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 .…”

“…However, our recent results did not suggest clear pro‐apoptotic effects of fluvastatin in rat mammary carcinomas (Kubatka et al . ). Statins demonstrably decrease the levels of one of the most important molecule implicated in angiogenesis, vascular endothelial growth factor (VEGF), and thereby inhibit capillary formation (Park et al .…”

“…In rat mammary carcinomas treated with fluvastatin, we have found a considerable decrease in VEGFR‐2 expression (Kubatka et al . ).…”