Molecular mechanisms regulating simvastatin-mediated inhibition of prostate cancer cellular functions in vitro and tumor growth in vivo
Al-Husein, Belal Abdelaziz Abdeljalil
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Prostate cancer is a leading killer in the United States. Lack of understanding of mechanisms of disease proliferation, progression and metastasis is a major hindrance in the proper management of this disease. Statins are drugs with known pleiotropy that could justify their introduction into various clinical conditions. Many clinical studies showed beneficial effects of statins in reducing prostate cancer progression and, to a lesser extent, development. In this research, the effect of simvastatin, a potent lipophilic statin, and the mechanism of its effect on prostate cancer cells is studied in vitro and in vivo. Results show promising effects of simvastatin on human prostate cancer proliferation, colony formation and migration, in both androgen-dependent and –independent disease. Effects were tested in vivo and showed a reduction of tumor size in simvastatin treated nude mice compared to controls. Mechanism of effect of simvastatin on cancer cell micrometastasis was also studied using ECIS, gene arrays, adhesion assays immunocytochemistry and western blotting and showed its effect on integrin αvβ3 activation and consequently adhesion, as well as impairment of tumor secreted factor effect, in addition to stabilization of endothelial barrier. In this research we also studied the effect of combination on proliferation and migration in vitro as well as on tumor growth in vivo and showed promising effect with a highly significant reduction of proliferation, migration and tumor growth compared to controls. In conclusion, our pre-clinical research shows beneficial effect of simvastatin alone or in combination with docetaxel in the management of prostate cancer and prevention of micrometastasis.