Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Stem cells more vulnerable to toxic chemotherapy when protective molecule is disabled

19.05.2004


Blocking a molecule that rids cells of potentially toxic molecules might make chemotherapy for leukemia more effective, but it could also leave healthy stem cells more vulnerable to toxic cancer treatment drugs



Inactivating a protective molecule in leukemic cells to make them more vulnerable to chemotherapy might also make healthy blood-forming cells more sensitive to the toxic effects of those same drugs. These findings have been published in the Journal of Biological Chemistry by investigators at St. Jude Children’s Research Hospital.
The St. Jude researchers based their conclusion on results of a study of a molecule whose normal function is to rid hematopoietic stem cells (HSCs) of a potentially toxic molecule called heme. HSCs are the "parent" cells in the bone marrow that give rise to red and white blood cells.

Heme is an oxygen-carrying molecule that is a key part of enzymes used by cells to extract energy from food and by red blood cells to carry oxygen to tissues. The basic building block of heme is porphyrin, which is toxic to cells when it accumulates in high concentrations, according to John Schuetz, Ph.D., associate member in the department of Pharmaceutical Sciences. Schuetz is senior author of the Journal of Biological Chemistry article, which also reports on studies of a molecule called BCRP (breast cancer resistance protein), which protects HSCs from excessive levels of heme.



In conditions of low oxygen, cells tend to compensate by making more heme molecules. But the cells must also protect themselves from excess heme by making BCRP, which is capable of binding to these oxygen-carrying molecules and transporting them out through the cell membrane. The ability of cells to rid themselves of excess heme is especially important in the bone marrow, where HSCs are normally exposed to a low-oxygen environment that stimulates the cells to produce more of this molecule.

In addition to heme, BCRP carries a variety of toxic and carcinogenic chemicals out of cells, including certain drugs used to treat leukemia. Researchers elsewhere are developing molecules to block BCRP in leukemic cells in order to make them more vulnerable to chemotherapy. However, drugs that block BCRP in leukemic cells would also block this molecule in healthy HSCs, leaving them vulnerable to toxic chemotherapy drugs.

"If that happens, the patient’s normal blood-forming cells could be depleted," Schuetz said. "And that would reduce the body’s ability to produce healthy red and white blood cells, which would certainly complicate the patient’s medical condition."

The investigators at St. Jude made their discoveries using bone marrow cells harvested from mice that either carried the gene for BCRP or lacked this gene. In conditions of low oxygen, the HSCs from mice that carried the gene for BCRP multiplied normally, apparently because they were able to rid themselves of excess heme. Similar cells from mice that lacked this gene--and thus could not protect themselves from excess heme--replicated only half as effectively as normal cells. When HSCs from mice carrying the BCRP gene were kept at normal oxygen levels and given the anti-leukemic drug mitoxantrone, 40 percent survived, apparently because they used BCRP to rid themselves of that drug. However, if HSCs from mice lacking the BCRP gene were exposed to mitoxantrone under the same conditions, none of the cells survived.


Other authors of the study were Partha Krishnamurthy, Sheng Zhou, Kelly E. Mercer and Brian P. Sorrentino (St. Jude); Douglas D. Ross, Takeo Nakanishi and Kim Bailey-Dell (University of Maryland School of Medicine); and Balazs Sarkadi (National Medical Center, Budapest Hungary). This work was supported in part by NIH, a Cancer Center support grant, a VA Merit Review Grant, ALSAC and a Howard Hughes International Scholarship.

St. Jude Children’s Research Hospital

St. Jude Children’s Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tennessee, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization.

Bonnie Cameron | EurekAlert!
Further information:
http://www.stjude.org

More articles from Life Sciences:

nachricht Bacteria as pacemaker for the intestine
22.11.2017 | Christian-Albrechts-Universität zu Kiel

nachricht Researchers identify how bacterium survives in oxygen-poor environments
22.11.2017 | Columbia University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Corporate coworking as a driver of innovation

22.11.2017 | Business and Finance

PPPL scientists deliver new high-resolution diagnostic to national laser facility

22.11.2017 | Physics and Astronomy

Quantum optics allows us to abandon expensive lasers in spectroscopy

22.11.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>