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 Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University

nachricht Direct conversion of non-neuronal cells into nerve cells
03.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz

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: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Behavior-influencing policies are critical for mass market success of low carbon vehicles

17.07.2018 | Power and Electrical Engineering

Plant mothers talk to their embryos via the hormone auxin

17.07.2018 | Life Sciences

Subaru Telescope helps pinpoint origin of ultra-high energy neutrino

16.07.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>