The antitumour activities of statins.

Abnormally elevated levels of serum cholesterol have been demonstrated to contribute to atherosclerosis and coronary artery disease. Statins, inhibitors of 3-hy-droxy-3-methylglutaryl coenzyme A (hmg-Coa) re-ductase, are efficient and widely used drugs in the treatment of lipid disorders, especially hypercholes-terolemia. In addition to their cholesterol-lowering effects, statins are reported to inhibit tumour cell growth 1,2. Statins are also known to synergistically enhance the effects of chemotherapy 3,4 and to overcome chemoresistance 5. Accordingly, statins prolong the survival of patients with hepatocellular carcinoma4, and they reduce the risk of colorectal cancer6 and breast cancer7.

Statins induce apoptosis and reduce cell invasiveness in various cell lines, including malignant glioma8, neuroblastoma9, myeloid leukemia10, and breast carcinoma11. Cancer cells overexpress hmg coa reductase 12. The chemopreventive activity of statins against cancer is suggested to depend on inhibition of hmg-Coa reductase in cholesterol synthesis and, thereby, cell growth 13. The Ras protein is important in the regulation of cell differentiation and proliferation. Statins are reported to inhibit the activation of ras 14. The products of the mevalonate pathway are necessary for diverse cellular functions, including the G1–S phase transition of cell proliferation and the formation of cell membranes 15. Statins may therefore inhibit cancer cell growth and lead to apoptotic cell death through their inhibition of the mevalonate pathway, although other mechanisms also have been suggested.

Interleukin-18 (il-18), a monocyte-derived cyto-kine, is upstream of the production of interferon γ from T cells and natural killer cells 16,17. Interleukin-18 is known to play an important role in regulating immune responses, exhibiting significant antitumour activity 18. The antitumour effects of il-18 are mediated by activation of natural killer cells and cytotoxic T lymphocytes 19. In a previous study, we found that the statins pravastatin, fluvastatin, and simvastatin induced production of il-18 by human monocytes 20,21. The effects of pravastatin, fluvastatin, and simvastatin were abolished by the addition of mevalonate, indicating the involvement of hmg-Coa reductase in the action of the tested statins.

Angiogenesis is characterized by the formation of new capillaries from existing vessels. It is well known that tumour growth and metastasis both require growth of new blood vessels 22,23. The statins lovastatin and cerivastatin are reported to inhibit tumour-induced angiogenesis by reducing metabolites of the mevalonate pathway that are pivotal in angio-genesis 24,25.

The foregoing observations suggest that the an-ticancer effect of statins depends on the apoptosis of cancer cells, the production of il-18 by monocytes, and the inhibition of angiogenesis. However, the effects of statins on cancer are not completely understood. Further experimental research will be useful in clarifying this complex relationship.