Cholesterol Drug May Hold Key to Cancer Prevention
Albany, July 6, 1999 – State Department of Health researchers have discovered how lovastatin, a drug routinely used for lowering cholesterol levels, has a novel and useful side effect, which is to lower the incidence of cancer. The key is the drug's previously unknown ability to interfere with the proteasome, cellular machinery that destroys proteins. Consequently, proteins that inhibit cell division, which are usually destroyed in tumor cells, accumulate and inhibit cell proliferation.
The finding, published in the July 6 issue of the Proceedings of the National Academy of Sciences, explains a beneficial side effect of lovastatin which underscores the proteasome as a target for cancer prevention. The drug's known mode of action is to inhibit the cholesterol biosynthesis pathway. Khandan Keyomarsi, Ph.D., and her team in the State Health Department's Wadsworth Center laboratories have discovered that the commonly prescribed form of the drug also inhibits the proteasome pathway.
The proteasome pathway is an intracellular garbage disposal for proteins that are no longer needed or are malformed. Among those proteins targeted for destruction are molecules called cyclin dependent kinase inhibitors (CKIs). CKIs act as brakes on cell division, and in their absence cancer's hallmark of runaway cell proliferation can occur. Cancer cells have low or undetectable levels of CKIs when compared to normal cells.
Dr. Keyomarsi's team treated human breast cancer cells with lovastatin and observed an increase in levels of two CKIs, p21 and p27. The increase prevented the further proliferation of the tumor cells. The novel discovery of Dr. Keyomari's study explains how lovastatin fits in with a class of drugs designed to target the proteasome and why lovastatin might be used as a cancer prevention agent.
Evidence that lovastatin might curb cancer has been mounting. A 1993 study of patients taking the drug to lower high cholesterol found a 33 percent reduction in their incidence of all cancer types, compared to the expected rate. A more recent report of test tube and animal studies suggested that it deters colon cancer. Neither investigation explained how the medication's known mode of action might account for its association with lower cancer incidence.
Dr. Keyomarsi, whose research is supported by the Department of Defense, National Institutes of Health, and the Cancer Research Foundation of America, earlier helped define the role of cyclins (accelerators of the cell cycle) in carcinogenesis and demonstrated the relationship between the level of cyclins and the aggressiveness or stage of breast cancer. She is a member of the Laboratory of Diagnostic Oncology of the Wadsworth Center, the multidisciplinary research and public health laboratory of the New York State Department of Health.