Statin Induces Apoptosis and Cell Growth Arrest in Prostate Cancer Cells

Abstract

Statins are a class of low molecular weight drugs that inhibit the rate-limiting enzyme of the mevalonate pathway 3-hydroxy-3-methylglutaryl-CoA reductase. Statins have been approved and effectively used to control hypercholesterolemia in clinical setting. Recent study showed statin's antitumor activity and suggested a potential role for prevention of human cancers. In this study, we did cell viability, DNA fragmentation, and terminal deoxynucleotidyl transferase -mediated dUTP nick-end labeling assays to evaluate the action of statins on prostate cancer cells and used Western blotting and RhoA activation assay to investigate the underlying molecular mechanism of action. Our data showed that lovastatin and simvastatin effectively decreased cell viability in three prostate cancer cell lines (PC3, DU145, and LnCap) by inducing apoptosis and cell growth arrest at G 1 phase. Both lovastatin and simvastatin induced activation of caspase-8, caspase-3, and, to a lesser extent, caspase-9. Both statins suppressed expression of Rb, phosphorylated Rb, cyclin D1, cyclin D3, CDK4, and CDK6, but induced p21 and p27 expression in prostate cancer cells. Furthermore, lovastatin and simvastatin suppressed RhoA activation and c-JUN expression, but not cyclooxygenase-2 expression. Our data showed that the antitumor activity of statins is due to induction of apoptosis and cell growth arrest. The underlying molecular mechanism of statin's action is mediated through inactivation of RhoA, which in turn induces caspase enzymatic activity and/or G 1 cell cycle. Future studies should focus on examining statins and other apoptosisinducing drugs (e.g., cyclooxygenase-2 inhibitors or curcumin) together to assess their efficacy in prevention of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(1):88 -94)

Combination Effect of δ-Tocotrienol and γ-Tocopherol on Prostate Cancer Cell Growth

“…3B) showed that LNCaP cells treated with d-T3 exhibited an increase in the number of apoptotic cells and the combination of d-T3 and g-Toc resulted in the onset of an especially massive apoptotic cell death. It is well known that anti-cancer activities of most anti-cancer agents mainly depend on cell cycle arrest and subsequent induction of apoptosis (20). The loss of cell cycle control in G1 has been implicated in tumor development and proliferation in prostate cancer cells (21).…”

Clinical Potential of Statins in Prostate Cancer Radiation Therapy

“…Cells located in the late G 1 and G 2 -M cell cycle phases are more sensitive to radiation-induced cell death, suggesting a potential mechanism of radiosensitisation induced by statins. It is thought that statins induce cell-cycle arrest in prostate cancer cells by reducing cell proliferation and arresting these cells in the G 1 phase of the cell cycle (51)(52)(53).…”

“…Hoque et al (51) Statin induces apoptosis and cell growth Data showed that the antitumor activity of statins is due arrest in prostate cancer cells.…”

Molecular mechanisms of toxicity of simvastatin, widely used cholesterol-lowering drug. A review

“…Simvastatin induces apoptosis in human skeletal muscle cells [39] and cardiac myocytes [40], human T, B and myeloma tumor cells [41], the TR-PCT1 pericyte cell line and freshly isolated human pericytes, which surround endothelial cells in precapillary arterioles, capillaries, and postcapillary venules [42], fibroblastlike synoviocytes derived from patients with rheumatoid arthritis [43], three human prostate cancer cell lines (PC3, DU145, and LnCap) [44]. In the PC3 cell line, simvastatin induces apoptosis or necrosis depending on concentration [45].…”

“…Simvastatin effectively decreases cell viability in three prostate cancer cell lines (PC3, DU145, and LnCap) by inducing apoptosis and cell growth arrest at G 1 phase and inducing activation of caspase-8, caspase-3, and caspase-9 [44]. In primary cultures of human skeletal muscle cells simvastatin increases caspase-9 and caspase-3 activities up to 3-fold, induces cell apoptosis as soon as 24 h following application, and as many as 80% of cells are died 48 h later [39].…”