Background: Statins are a class of drugs that inhibits HMG-CoA reductase, a rate liming enzyme in cholesterol synthesis. Simvastatin, a widely used generic drug for preventing cardiovascular events inhibit inflammation and stabilize atherosclerotic plaques. Growing body of evidences suggest that statins have the potential to reduce the risk of many cancer types.

Objectives and Hypothesis: Our long-term goal is to enable the development of new and innovative therapeutics for prostate cancer through better understanding of the molecular mechanisms regulating prostate cancer growth and bone metastasis. In prostate cancer cells, simvastatin is known to induce apoptosis. Akt, a multitask signaling molecule, is the major survival kinase activated in cancer cells. Our central hypothesis is that treatment with simvastatin will inhibit Akt affecting prostate cancer cell function, tumor growth and metastasis. The rationale for the proposed research is that, once it is known mechanistically how simvastatin regulates prostate cancer cell function, it is likely that prostate tumor growth and metastasis can be downregulated therapeutically utilizing simvastatin using a novel drug-repurposing strategy. This would be of singular importance in the management of this disease.

Experimental Design and Results: In the current study, we sought to investigate the pleiotropic effects of simvastatin on major signaling pathways in prostate cancer cells with respect to the regulation of cellular functions such as migration, proliferation, colony/foci formation and invasion, along with its already known effects on apoptosis. Time- and dose-effects of simvastatin on LNCaP (androgen-dependent) and PC-3 (androgen-independent) cells indicated that treatment with as low as 25µM simvastatin was sufficient to inhibit serum-stimulated activation of Akt-mTOR and cRaf-ERK pathways. Akin to this, treatment with 25µM simvastatin significantly inhibited serum- and EGF-induced cell migration, invasion, colony formation and proliferation. Simvastatin-mediated effects on cell migration and colony formation was rescued by adenovirus-mediated expression of constitutively active Akt (myristoylated Akt) in androgen-independent prostate cancer cells lines such as PC3 and LnCAP C4-2. A xenograft model performed in nude mice exhibited reduced PC3 prostate tumor growth with simvastatin treatment (2mg/kg body weight/day for 2 weeks) demonstrating the therapeutic potential of simvastatin for prostate cancer therapy.

Conclusions and Future Directions: Our findings suggest a link between simvastatin and Akt/ERK signaling in the regulation of prostate cancer growth and metastasis. Further investigation is currently underway in our laboratory to unravel the molecular mechanisms on simvastatin-mediated effects on prostate cancer leading to tumor growth and bone metastasis in vivo using transgenic mouse models such as AKt+ and TRAMP+ mice. We also plan to undertake a clinical study on patients with prostate cancer who were on statin treatment prior to and after diagnosis and analyze biopsy specimen from these patients. A prospective study will look at the role statins in prostate cancer prevention and/or on management. Our ultimate aim is to investigate if statins can be used as an adjuvant drug in the treatment of patients already diagnosed with prostate cancer.

Citation Information: Clin Cancer Res 2010;16(14 Suppl):B47.