Viagra Increases Potency of Anticancer Treatment While Preventing Heart Damage

A drug cocktail that combines the potent anticancer agent doxorubicin (DOX) with the well-known impotence drug Viagra (sildenafil) has been shown to be a potent inhibitor of prostate cancer both in vitro and in a mouse model of the disease.

Although in use for more than 40 years as a primary chemotherapy drug, DOX is known to cause serious heart problems. To prevent these, doctors may limit the amount of DOX given to each patient so that the total amount a patient receives over her or his entire lifetime is 550 milligrams per square meter, or less. The necessity to stop treatment to protect the patient from heart disease may diminish the usefulness of DOX in treating cancer.

To eliminate possible cardiac damage investigators at the Virginia Commonwealth University School of Medicine (Richmond, USA) have combined DOX with sildenafil. They based this on approach on findings from studies that showed that as well as treating erectile dysfunction, sildenafil is effective in treating the rare disease pulmonary arterial hypertension (PAH). Sildenafil relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure.

Sildenafil counteracts impotence by blocking the enzyme phosphodiesterase 5 (PDE5), which can end erections prematurely. Because PDE-5 is primarily distributed within the arterial wall smooth muscle of the heart, lungs, and penis; sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body.

Results published in the September 30, 2010, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) revealed that cotreatment with sildenafil enhanced DOX-induced apoptosis in PC-3 and DU145 prostate cancer cells, which was mediated by enhanced generation of reactive oxygen species, up-regulation of caspase-3 and caspase-9 activities, reduced expression of Bcl-xL, and phosphorylation of Bad. Overexpression of Bcl-xL or dominant negative caspase 9 weakened the synergistic effect of sildenafil and DOX on prostate cancer cell killing.

Treatment with sildenafil and DOX in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. The reduced tumor size was associated with amplified apoptotic cell death and increased expression of activated caspase 3. Doppler echocardiography showed that sildenafil treatment prevented DOX-induced ventricular dysfunction.

"We believe sildenafil could be an excellent candidate for incorporation into cancer treatment protocols – with the potential of enhancing the antitumor efficacy, while protecting the heart against both short term and long term damage from doxorubicin,” said senior author Dr. Rakesh C. Kukreja, professor of cardiology at the Virginia Commonwealth University School of Medicine. "My team and I are hoping to move the research forward to a clinical trial and plans are under way to do so."

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Virginia Commonwealth University School of Medicine