Simvastatin as an immunomodulator and anti-myeloma agent – epidemiological, in vitro and murine model studies

Introduction – Simvastatin (SIM), a member of the statin family, is commonly used to lower blood cholesterol levels, particularly low-density lipoprotein. Statins inhibit the action of hydroxy-methyl-glutaryl-coenzyme A reductase, an important enzyme in the synthesis of cholesterol and isoprenoids; they also have anti-inflammatory effects and can regulate membrane synthesis in cancer cells. Preliminary evidence suggests an association between SIM use and reduced cancer incidence. SIM’s anti-cancer efficacy in vivo has been shown in studies on several solid tumors, but little is known about its effects on hematological cancers, such as Multiple Myeloma (MM). Methods – Initially, we searched for such as an association in a large community database and observed a significantly lower MM incidence among SIM users. We proceeded to test the effect of SIM on both murine and human MM cell lines and the tested the effect of long-term SIM treatment on development of MM in an animal model. Results – SIM exposure led to apoptosis in both murine and human MM cell lines. We show that long-term intake of SIM reduced tumor load and positively impacted bone marrow CD8+ T levels as well as cell-mediated anti-myeloma cytotoxicity. SIM treatment also elevated the total IgA and IgG serum concentrations in healthy mice. Conclusions – These results suggest that SIM, which many adults use to control cholesterol levels, may play a dual role in the management of MM, by influencing membrane synthesis in myeloma cells leading to apoptotic cell death and enhancing the T-cell mediated anti-tumor cell response in MM.