Protein protecting brain from toxins also blocks some chemotherapy from reaching tumors
St. Jude studies showing that Mrp4 limits penetration of topotecan suggest that blocking this protein might increase access of anti-cancer drugs to tumor sites and improve treatment of brain cancer
A protein called Mrp4 blocks the access of the anti-cancer drug topotecan into the brain by transporting this agent back into the bloodstream, thus reducing the ability of this agent to reach tumors. Results from a series of studies by investigators at St. Jude Childrens Research Hospital are published in a recent issue of Molecular and Cellular Biology (MCB).
The St. Jude team, which developed a mouse model lacking the Mrp4 protein, says study results in both mice and tissue cultures suggest that the therapeutic efficacy of drugs targeting central nervous system tumors might be improved by inhibiting this protein, a type of molecule called an ABC-dependent transporter.
The study showed that Mrp4 works at two levels: by binding to topotecan and transporting it away from the brain Mrp4 restricts the drugs penetration into the brain from the bloodstream; and it protects brain cells from accumulating toxic levels of topotecan molecules that do escape the bloodstream. "The ability of Mrp4 to protect the brain from toxins can be a liability in people with brain cancer when this protein also blocks therapeutic drugs from reaching CNS tumors," said John Scheutz, Ph.D., an associate member of the St. Jude Department of Pharmaceutical Sciences. Schuetz is senior author of the article.
The investigators discovered that when topotecan was injected into the veins of specially bred mice that lack Mrp4, the drug accumulated to greater than normal levels in the brain tissue and the fluid that surrounds the brain--the cerebrospinal fluid (CSF). The finding strongly suggests that the natural role of Mrp4 is to block the passage of certain toxic molecules, which chemically resemble topotecan, from leaving the bloodstream and entering the brain. The cells lining the walls of brain capillaries are tightly joined to form a barrier that prevents most substances from leaving the blood. This cellular barrier, called the blood-brain barrier, prevents certain substances from leaving the bloodstream and entering the brain. Mrp4 in the blood-brain barrier also prevents substances from entering the brain by transporting them back into the blood as they pass into the cells of this barrier.
Using antibodies against Mrp4 the investigators found that this protein is located in the brains capillaries as well as in membranes of the choroid plexus--the folds within the brain ventricles that make and release CSF. "This dual location for Mrp4 is unusual for this type of transporter," Schuetz said. "It suggests that Mrp4 blocks specific molecules from leaving the capillaries. And if such molecules slip out of the blood into the choroid plexus, Mrp4 shuttles them back out of the brain and into the blood before they can cause damage."
The investigators also showed that isolated cells that were modified to over-express Mrp4 did not accumulate as much topotecan as cells lacking this protein. This is strong evidence that over-expression of Mrp4 in tumors contributes to topotecan resistance in patients. "Our work has important implications for therapies that target brain tumors with specific types of drugs that are transported by Mrp4," Schuetz said. "There is an expanding array of these types of drugs being developed; and unless there is a way to block Mrp4 when giving these agents, the effectiveness of these new agents could be significantly compromised."
Other authors of this study are Markos Leggas, Masashi Adachi, Daxi Sun, Guoqing Du, Kelly E. Mercer, Yanli Zhuang, John C. Panetta, Brad Johnston and Clinton F. Stewart (St. Jude); George L. Scheffer and Rik J. Scheper (VU Medical Center, Amsterdam, The Netherlands); and Peter Wielinga (The Netherlands Cancer Institute, Amsterdam).
Bonnie Cameron | EurekAlert!
The most recent press releases about innovation >>>
Die letzten 5 Focus-News des innovations-reports im Überblick:
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...