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
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 Heitman's colleague Dr. Charles Hemenway.
Heitman and Hemenway, both researchers in Duke's Comprehensive
Cancer Center, reported their findings in the August 2nd issue
of the Journal of Biological Chemistry. They found that three
drugs given to stop organ transplant rejection--cyclosporine (Sandimmune),
FK506, and rapamycin--also block the cellular pump that expels
cancer chemotherapy drugs. But the drugs block the pump by different
Antirejection Drugs Prevent Resistance via Different Mechanisms
Previously, scientists believed the antirejection 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 their suppressant
effects on 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."