Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Chemical switch determines if healthy cells are killed by chemotherapy

04.10.2002


Investigators at Washington University School of Medicine in St. Louis have discovered a mechanism that helps explain why healthy cells are not killed by DNA-damaging cancer chemotherapy drugs. The findings are published in the Oct. 4 issue of the journal Cell.



DNA-damaging agents are the most common kind of drugs used to treat cancer. Like most chemotherapy drugs, these are carried in the blood and travel throughout the body. They work by irreparably gumming up DNA in rapidly dividing tumor cells. That damage then triggers the cells to self-destruct through a natural process known as apoptosis, or active cell death.

The drugs also can harm rapidly dividing healthy cells, such as those in the hair follicles, but most healthy cells are unaffected. It is not known why these drugs do not trigger apoptosis in healthy cells.


"The standard answer is that tumor cells are dividing and normal cells are not," says Steve J. Weintraub, M.D., assistant professor of surgery, division of urologic surgery, of medicine and of cell biology and physiology. "But that’s an observation, not an explanation."

The study led by Weintraub found that healthy, nondividing cells have a biochemical switch that when triggered allows apoptosis. The switch is found in a protein that blocks apoptosis known as Bcl-xL.

"Our findings show that if Bcl-xL is inactivated through a chemical process known as deamidation, DNA-damaging chemotherapy will kill even healthy cells," says Weintraub, who is a researcher with the Cellular Proliferation research program at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

The study focuses on a family of proteins known as Bcl-2, which play a central role in both promoting and inhibiting apoptosis. The investigators first exposed cancer cells from bone, ovarian and other tumors to the anti-cancer drug cisplatin. When they looked at the Bcl-2 proteins from the cells that had died by apoptosis, they found that in each case one member of the Bcl-2 family, the protein Bcl-xL, had been modified by deamidation.

Deamidation makes slight changes in two amino acids in the Bcl-xL protein. As if someone had thrown a switch, those changes alter the shape of Bcl-xL and thereby inactivate it. In its active state, Bcl-xL is tightly joined with another Bcl-2 protein that when free triggers apoptosis. When Bcl-xL is switched off through deamidation, it releases the second protein, and apoptosis can proceed.

The researchers also exposed a line of healthy, nondividing human fibroblasts and several lines of mouse fibroblasts to cisplatin. In some of the cells, the investigators had artificially inactivated the Bcl-xL protein. They found that cells with normal Bcl-xL were not affected by the drug, while those with the inactive Bcl-xL protein died by apoptosis, indicating they were now susceptible to cisplatin.

"Our findings show that normal cells somehow suppress the signal that throws the switch and avoid self-destructing," says Weintraub. They also suggest that tumor cells that suppress the same signal also might be resistant to chemotherapy drugs, he says.

Weintraub is now studying the nature and regulation of the signal that targets Bcl-xL.

Darrell E. Ward | EurekAlert!
Further information:
http://medinfo.wustl.edu/

More articles from Health and Medicine:

nachricht Lung images of twins with asthma add to understanding of the disease
06.12.2019 | University of Western Ontario

nachricht Between Arousal and Inhibition
06.12.2019 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Developing a digital twin

University of Texas and MIT researchers create virtual UAVs that can predict vehicle health, enable autonomous decision-making

In the not too distant future, we can expect to see our skies filled with unmanned aerial vehicles (UAVs) delivering packages, maybe even people, from location...

Im Focus: The coldest reaction

With ultracold chemistry, researchers get a first look at exactly what happens during a chemical reaction

The coldest chemical reaction in the known universe took place in what appears to be a chaotic mess of lasers. The appearance deceives: Deep within that...

Im Focus: How do scars form? Fascia function as a repository of mobile scar tissue

Abnormal scarring is a serious threat resulting in non-healing chronic wounds or fibrosis. Scars form when fibroblasts, a type of cell of connective tissue, reach wounded skin and deposit plugs of extracellular matrix. Until today, the question about the exact anatomical origin of these fibroblasts has not been answered. In order to find potential ways of influencing the scarring process, the team of Dr. Yuval Rinkevich, Group Leader for Regenerative Biology at the Institute of Lung Biology and Disease at Helmholtz Zentrum München, aimed to finally find an answer. As it was already known that all scars derive from a fibroblast lineage expressing the Engrailed-1 gene - a lineage not only present in skin, but also in fascia - the researchers intentionally tried to understand whether or not fascia might be the origin of fibroblasts.

Fibroblasts kit - ready to heal wounds

Im Focus: McMaster researcher warns plastic pollution in Great Lakes growing concern to ecosystem

Research from a leading international expert on the health of the Great Lakes suggests that the growing intensity and scale of pollution from plastics poses serious risks to human health and will continue to have profound consequences on the ecosystem.

In an article published this month in the Journal of Waste Resources and Recycling, Gail Krantzberg, a professor in the Booth School of Engineering Practice...

Im Focus: Machine learning microscope adapts lighting to improve diagnosis

Prototype microscope teaches itself the best illumination settings for diagnosing malaria

Engineers at Duke University have developed a microscope that adapts its lighting angles, colors and patterns while teaching itself the optimal...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

The Future of Work

03.12.2019 | Event News

First International Conference on Agrophotovoltaics in August 2020

15.11.2019 | Event News

Laser Symposium on Electromobility in Aachen: trends for the mobility revolution

15.11.2019 | Event News

 
Latest News

Solving the mystery of carbon on ocean floor

06.12.2019 | Earth Sciences

Chip-based optical sensor detects cancer biomarker in urine

06.12.2019 | Life Sciences

A platform for stable quantum computing, a playground for exotic physics

06.12.2019 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>