'Erectile Dysfunction' Drugs Heighten Natural Anti-cancer Activity

Tests at Hopkins on mice with implanted colon and breast tumors showed that tumor size decreased two- and threefold in sildenafil-treated animals, compared to mice that did not get the drug. In mice engineered to lack an immune system, tumors were unaffected, proof of principle, the scientists say, that the drug is abetting the immune system's own cellular response to cancer.

In a report published in the Nov. 27 issue of the Journal of Experimental Medicine, the Hopkins team says boosted levels of the chemical messenger nitric oxide appear to dampen the effects of a specialized cell that diverts the immune system away from tumors, allowing swarms of cancer-attacking T-cells to migrate to tumor sites in the rodents.

Lab-grown cancer cells treated with sildenafil showed similar results, as did tissue samples taken from 14 head and neck cancer and multiple myeloma patients.

Sildenafil, marketed under the trade name Viagra, is one of a class of drugs used to treat erectile dysfunction in millions of men, and in recent years, its ability to stimulate the production of NO has been investigated by experts in diseases linked to the activity of blood vessels and blood components.

The new Hopkins study homes in on a tactic used by cancers to avoid detection by the immune system by turning elements of that system to its own advantage, says Ivan Borrello, M.D., assistant professor at the Johns Hopkins Kimmel Cancer Center.

Borrello and his colleagues found that tumors exploit nitric oxide-producing immune cells to create a sort of "fog" that keeps them hidden from white blood cells (T-cells) that mount attacks on tumors.

These NO-producing cells, a.k.a. myeloid-derived suppressor cells (MDSCs), normally use nitric oxide to help bring the immune system back down to surveillance levels after an "attack mode" response to foreign material.

The impotence drugs seem to reverse this process, stopping the production of nitric oxide by MDSCs thereby allowing other immune cells to "see" the cancer and attack it, says Paolo Serafini, Ph.D., a research fellow in Borrello's laboratory and lead author on the paper.

Nitric oxide is infamous among city dwellers as a component of air-polluting smog, but is gaining importance in medical research for its cell-signaling duties and its ability to divert soldiering T-cells that patrol and protect.

The Hopkins team also analyzed gene expression patterns of the myeloid-derived suppressor cells and found that sildenafil blocked two genes regulating enzymes -- arginase and nitric oxide synthase -- which are key to triggering immune suppression via MDSCs. Borrello's team found that the arginase enzyme, which metabolizes a dietary supplement called L-arginine, also contributes to dampening the immune system through MDSCs much like nitric oxide, and its production can be reversed by sildenafil.

"Impotence drugs won't cure cancer," Borello cautioned, "but could be used in addition to standard chemotherapy or immunotherapy treatments."

The investigators are planning human studies to begin in the next year.

Funding for the study was provided by the Italian Association for Cancer Research.

Coauthors include Kristin Meckel, Michael Kelso, Kimberly Noonan, Joseph Califano, and Wayne Koch from Johns Hopkins; and Luigi Dolcetti and Vincenzo Bronte from the Istituto Oncologico Veneto in Padua, Italy.