Statins are drugs that reduce cholesterol in the management and prevention of cardiovascular disease. But according to a growing body of research gathered over the past decade, statins also have potential for use in cancer management.
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"Specifically, when the proteasome is prevented from activating by lovastatin, the cell cycle brakes p21 and p27 do not degrade, but remain in the cell and stop the unregulated cell growth that characterizes cancer cells," she said. The cyclin-dependent kinase inhibitors p21 and p27 are known to inhibit cancer cell growth.
This new research is published in the 2003 Proceedings of the American Association for Cancer Research. Keyomarsi and colleagues had previously discovered that the unconverted form of lovastatin stops cells from activating the proteasome and from degrading p21 and p27, arresting cancer cell growth. In her new work, she compared lovastatins action to that of farnesyl transferase inhibitors and another group of drugs, proteasome inhibitors, both of which are known to inhibit the proteasome pathway. Keyomarsi found that they all worked through the same proteasome-inhibiting mechanism and all inhibit cell growth. The proteasome pathway is a relatively new target for cancer drugs; the first proteasome inhibitor, Velcade, was approved in mid-May for the treatment of refractory multiple myeloma (see related story, p. 845).
Other researchers have shown that at higher concentrations, statins are not just cytostatic, but can also prevent metastasis and normal tissue invasion of cancer cells. Earlier work by Christophe Denoyelle, Ph.D., and colleagues at CNRS and INSERM in France showed that a potent analogue of lovastatin, cerivastatin (Baycol), inhibited the signaling pathways involved in the metastasis and invasion of highly invasive breast cancer cell lines. And other researchers have shown that statins increase the radiosensitivity of cancer cells.
Keyomarsis interest in the relationship of the cell cycle to breast cancer dates back to 1993, when she published a paper demonstrating that cancer disrupts the cell cycle, inducing abnormal cells to overexpress several regulatory molecules. Late last year, in a retrospective study of 395 patients, her team showed that breast cancer patients whose tumors overexpressed a low-molecular weight form of one of the cell cycle molecules, cyclin E, had very poor prognoses. "This abnormal form of cyclin E gives the go signal continuously to cells to divide," she said.
But how did statins become connected with fighting cancer in the first place? "When statins were first tested in the clinic for their cholesterol-lowering properties, researchers feared that the drugs might increase the risk of liver cancer, as had been seen in high-dose rat studies," said Jim Dimitroulakos, Ph.D., career scientist and statin researcher at the Ottawa Regional Cancer Centre in Canada. But a retrospective study of patients with cardiovascular disease published in 1993, and others since, showed that cancer incidence in statin-treated patients was actually lower than normal, he added. Dimitroulakos own work has demonstrated that high doses of statins can cause programmed cell death, or apoptosis, in certain tumor types.
Over the past decade, numerous in vitro and preclinical studies have shown that various statins have antiproliferative, antiangiogenic, radiosensitizing, and pro-apoptotic properties in many types of cancer cells. Although the U.S. Food and Drug Administration pulled the most potent statin, cerivastatin, from the market in 2001 because of muscle and liver toxicities, research with the drugs in cancer has continued, mostly with the other statin family members. "Even though cerivastatin is more efficacious than lovastatin, its more toxic and therefore its therapeutic value may actually be less than lovastatin and other statins," said Dimitroulakos.
Numerous in vitro studies have shown that statins have inhibitory effects on breast cancer cells, acute myeloid leukemia (AML) cells, multiple myeloma cells, squamous cell carcinoma cells, and lung cancer cellswith especially toxic effects in AML and squamous cell carcinoma. Statins have also been shown to inhibit metastasis in rat lymphoma and mouse melanoma models, and in hepatic metastases of colon tumors in mice. Although researchers agree that statins have anti-cancer activity, not everyone agrees with Keyomarsi that the target of the drugs in cancer is the proteasome. Dimitroulakos research shows that statins induce apoptosis in AML and squamous cell cancers not by growth inhibition via the proteasome, as Keyomarsi demonstrates, but by targeting the HMG-CoA reductase enzyme in the cholesterol synthesis pathway.
Dimitroulakos concedes that growth inhibition in other tumor typessuch as breast cancermay indeed target the proteasome. "Many drugs are specific to only certain cell types and not others," he said. Indeed, Kedar Prasad, Ph.D., professor of radiology at the University of Colorado Health Sciences Center in Denver, has shown that mevastatin induces cellular degeneration and decreases viability of neuroblastoma cells by inhibiting proteasome activity. An earlier study by Dimitroulakos showed that the HMG-CoA enzyme mediates retinoic acids growth inhibitory effects in human neuroblastoma cells.
Recently, another group reported research that lends support to Dimitroulakos findings that statins work in cancer via the cholesterol pathway. In the May 1 issue of Blood, Deborah Banker, Ph.D., and her team at the Fred Hutchinson Cancer Research Center, Seattle, demonstrated that statins kill AML cells directly via cholesterol modulation. Commenting on that work, Keyomarsi noted that because certain cancer cells contain higher levels of cholesterol, some may be more sensitive to cholesterol or the end-products of the cholesterol pathway. Banker, a staff scientist in clinical research, agrees. "The extent of toxicity in AML cells is affected by the availability of extracellular lipoproteins, further suggesting that cellular cholesterol is critical to cell survival in particular AMLs," said Banker.
Apart from exactly how statins work in cancer, both Keyomarsi and Dimitroulakos agree that the effects are amplified when combined with other chemotherapeutic drugs, such as 5-fluorouracil and epidermal growth factor receptor inhibitors. Moreover, they said that the high levels of statins needed to induce apoptosis rather than inhibit cell growth make statins more appropriate for use in combination therapy with other cytotoxic agents because of toxicity concerns.
Dimitroulakos is conducting preclinical studies with various combinations. A small phase I trial is under way at the Dartmouth-Hitchcock Medical Center, Lebanon, N.H., for refractory blood cancers using once-daily atorvastatin. Study director Raymond Perez, M.D., said that although it is still early, he has seen "some hints of beneficial activity" in patients on this statin alone.
Because the statins are cytostatic, according to Keyomarsi, and pro-apoptotic, according to Dimitroulakos, both see a potential role for them in the future treatment of a number of cancers when used in combination with other drugs. Keyomarsi envisions that it might be possible to target normal cells with statins to cause them to "rest" while cytotoxic agents are used to kill only dividing cancer cells. In addition to having potential for cancer prevention and treatment, statins are also being studied for their neuroprotective capability as a possible therapeutic or preventive agent in Alzheimers disease, and for their angiogenic effects in cardiovascular disease.
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