DURHAM, N.C. -- Researchers at the Howard Hughes Medical Institute at Duke
University Medical Center have shown how drugs that stop organ transplant
rejection also partially reverse drug resistance in certain cancer cells.
Such resistance, which thwarts cancer chemotherapy, is a principal cause
of death for cancer patients. The scientists have identified a new target
to stop drug resistance in cancer cells. The researchers believe the finding
will help scientists develop new compounds to prevent drug resistance in
patients with cancer, but without compromising the immune system.
"We may have identified an Achilles' heel in the body's natural reaction
in expelling toxic drugs," said geneticist Dr. Joseph Heitman, the
study's principal investigator.
The research was supported in part by the National Institute of Environmental
Health Sciences and a Rhone Poulenc Rorer Hematology Scholar award to colleague
Dr. Charles Hemenway.
Heitman and Hemenway, both researchers in Duke's Comprehensive Cancer Center,
reported their findings in the Aug. 2 issue of the Journal of Biological
Chemistry. They found that three drugs given to stop organ transplant rejection
-- cyclosporin, FK506, and rapamycin -- also block the cellular pump that
expels cancer chemotherapy drugs. But it turns out the drugs block the pump
by different mechanisms.
Previously, scientists believed the anti-rejection drugs acted like sludge
in a gas tank, clogging the pump mechanism. But the Duke scientists showed
that FK506 and rapamycin also tie up a separate protein, called FKBP12,
which they showed is an essential activator for the pump to work correctly.
In other words, the two drugs primarily halt the cellular pump by removing
a vital part, like a valve from a car's fuel pump.
"Cyclosporin-related drugs are now being tested for their ability to
reverse chemotherapy resistance in cancer patients, but little had been
known about how these common immune suppressants work in this setting,"
Heitman said. "Our findings shed light on a new mechanism that can
be exploited to overcome drug resistance in cancer cells."
The researchers tested their ideas using common baker's yeast as a model
organism, because basically the same multidrug resistance pump (MDR) is
found in yeast, animals and people, Heitman said.
The MDR pump is a large protein that acts like a pore in the cell surface.
It selectively pumps out toxic chemicals that find their way inside the
cell. Normally, the MDR pump protects the cell against poisons, but resistant
cancer cells have many times the normal amount of MDR protein to protect
them from chemotherapy drugs. These cells work overtime, expelling chemotherapy
drugs that would normally kill a cancerous tumor and allowing runaway cell
growth to continue. Physicians and researchers have been searching for ways
to clog the MDR pump for many years. But many promising MDR blockers have
turned out to be toxic in the doses needed for them to be effective.
"The MDR protein is so big that its FKBP12 component is like a flea
on an elephant's back," said Heitman. "But it appears to be crucial.
Based on our experiments, we think FKBP12 could help open and close the
pump. When FKBP12 is missing, the pump may not be able to open and close
properly to expel the drugs from the cell."
The researchers say the findings could change the way doctors evaluate
potential MDR-blocking drugs. Such drugs would be similar in shape to FK506
and rapamycin, but without suppressing the immune system. Heitman says such
compounds have already been found, but have not yet been tested in people.
"It may be that non-immunosuppressive compounds that block FKBP12
will turn out to be better at overcoming drug resistance in tumor cells,"
Heitman said. "Simply jamming the pump mechanism may not be enough."