Sildenafil and other "impotence drugs" that boost the
production of a gassy chemical messenger to dilate blood
vessels and produce an erection now also show promise in
unmasking cancer cells so that the immune system can
recognize and attack them, say scientists at the
Hopkins Kimmel Cancer Center.
Tests at Johns 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 Johns 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; in recent years, its ability to
stimulate the production of nitric oxide has been
investigated by experts in diseases linked to the activity
of blood vessels and blood components.
The new Johns 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, 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 nitric oxide-producing cells, also known as
myeloid-derived suppressor cells, or MDSCs, normally use
nitric oxide to help bring the immune system back down to
surveillance levels after an "attack mode" response to
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, said Paolo Serafini, a research fellow in Borrello's
laboratory and lead author on the paper.
Nitric oxide may be infamous among city dwellers as a
component of air-polluting smog, but it is gaining
importance in medical research for its cell-signaling
duties and its ability to divert soldiering T-cells that
patrol and protect.
The Johns 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 — that 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. Co-authors are Kristin
Meckel, Michael Kelso, Kimberly Noonan, Joseph Califano and
Wayne Koch, all of Johns Hopkins; and Luigi Dolcetti and
Vincenzo Bronte, of the Istituto Oncologico Veneto in