A protein found on the surface of drug-resistant cancer cells that pumps away chemotherapy treatments also removes a bioluminescent agent widely used in imaging research, according to a new study from scientists at the Mallinckrodt Institute of Radiology at Washington University School of Medicine in St. Louis.
David Piwnica-Worms, M.D., Ph.D., professor of molecular biology and pharmacology and of radiology, calls the result, published in late January in the early online edition of Proceedings of the National Academy of Sciences, a “two-edged sword.”
“This finding gives us a non-invasive, real-time way to monitor the effects of new treatments that may be able to overcome cancer drug resistance in live animal models because it’s likely that if the imaging agent is expelled from cells, chemotherapy agents would be removed, too,” explains Piwnica-Worms, who is director of Washington University’s Molecular Imaging Center. “But it also means that basic scientists who use this imaging agent are going to have to consider the possibility that interactions between the Pgp protein and the imaging agent may be affecting their results.”
The imaging agent, coelenterazine, is produced by microorganisms in the sea and passed through several marine organisms in the food chain. Coelenterazine glows when it interacts with Renilla luciferase, a protein derived from the sea pansy. Scientists can detect this glow in genetically modified organisms with non-invasive imaging devices.
Andrea Pichler, Ph.D., a postdoctoral fellow in Piwnica-Worms’ laboratory, led the study that identified coelenterazine’s interactions with MDR1 P-glycoprotein (Pgp), the cancer drug-resistance protein.
David Piwnica-Worms
“This protein’s abilities are a clinically validated and feared reality,” Piwnica-Worms says. “When the MDR1 form of Pgp becomes active, it doesn’t just block one chemotherapeutic treatment, it provides resistance to a whole swath of treatments.”
Pgp pumps drugs out of cancer cells or off their surfaces, making it difficult for the chemotherapeutic agents to build up to levels where they can kill the cells. Coelenterazine has similar physical and chemical properties to the cancer drugs, making it possible for Pgp to catch it and push it away.
Piwnica-Worms plans to develop methods for using the new connection to study regulation of Pgp in live animals and to rapidly test the abilities of new drugs. The link may also help scientists interested in better understanding the food chain in marine ecosystems, where coelenterazine is a widespread component.