Abstract
Prostate cancer is the second leading cause for cancer-associated death among men in the United States. More recently, there has been a renewed interest in the potential therapeutic benefits of statins for cancer. Simvastatin, a widely used generic drug for preventing cardiovascular events, is well known for its effects on cellular proliferation and inflammation, two key processes that also determine the rate of tumor growth. While a growing body of evidence suggests that statins have the potential to reduce the risk of many cancers, there are discrepancies over the pro- and anti-cancer effects of statins on cancers. In the current study, we sought to investigate the effects of simvastatin on the Akt pathway in prostate cancer cells with respect to the regulation of various cell functions in vitro and tumor growth in vivo. Time- and dose-effects of simvastatin on LNCaP (androgen-dependent) and PC3 (androgen-independent) cells indicated that treatment with as low as 25 µM simvastatin was sufficient to inhibit serum-stimulated Akt activity. Akin to this, treatment with simvastatin significantly inhibited serum-induced cell migration, invasion, colony formation and proliferation. Simvastatin-mediated effects on colony formation was rescued by Adenovirus-mediated expression of constitutively active Akt (myristoylated Akt) in PC3 cell lines. A PC3 xenograft model performed in nude mice exhibited reduced tumor growth with simvastatin treatment associated with decreased Akt activity and reduced PSA levels. Our findings demonstrate the therapeutic benefits of simvastatin for prostate cancer and suggest a link between simvastatin, regulation of Akt activity and PSA expression in prostate tumors.
- Received September 7, 2010.
- Revision received November 4, 2010.
- Accepted November 5, 2010.
- The American Society for Pharmacology and Experimental Therapeutics