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 Fast-tracking T cell therapies with immune-mimicking biomaterials
16.01.2018 | Wyss Institute for Biologically Inspired Engineering at Harvard

nachricht Dengue takes low and slow approach to replication
12.01.2018 | Duke University

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: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

Im Focus: A thermometer for the oceans

Measurement of noble gases in Antarctic ice cores

The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

White graphene makes ceramics multifunctional

16.01.2018 | Materials Sciences

Breaking bad metals with neutrons

16.01.2018 | Materials Sciences

ISFH-CalTeC is “designated test centre” for the confirmation of solar cell world records

16.01.2018 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>