Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Targeting leukemic stem cells by Bcl-2 inhibition

20.11.2006
Study in laboratory cell cultures, patient samples shows promise

Researchers at The University of Texas M. D. Anderson Cancer Center have found, in laboratory studies, that the experimental drug ABT-737 which has shown promise in some cancers, can destroy acute myeloid leukemia (AML) blast, progenitor and even stem cells that are often resistant to standard chemotherapy treatment.

The drug was powerful in its own right, the researchers say, but they found that some AML cells were themselves resistant to ABT-737, so they added another drug that knocked out this secondary resistance. Together, these agents may provide a powerful therapy against AML, and could form the basis of a new way to treat the cancer, say the scientists, whose study was published in the November 14 issue of the journal, Cancer Cell.

"The combination of these two experimental drugs provides the highest synergistic action I have ever seen against acute myeloid leukemia cells," said the study's lead author, Michael Andreeff, M.D., Ph.D., professor in the Departments of Stem Cell Transplantation and Leukemia.

... more about:
»ABT-737 »AML »Andreeff »Bcl-2 »Mcl-1 »Protein »chemotherapy »leukemia

Although the study was done in laboratory cell cultures and AML cells obtained from patients, Andreeff said he hopes that a combination of these two agents could be tested in eligible patients when they receive standard chemotherapy treatment. "ABT-737 would overcome resistance to chemotherapy that we often see in AML therapy, and the second drug would overcome resistance to ABT-737," he said.

"ABT-737 represents a completely new class of agents that could have a major impact on a number of cancers, and we have now seen that AML will likely be among them," Andreeff added.

The successful use of ABT-737 in animal models of human small-cell lung cancer and cancers of the lymph system were reported in 2005 by researchers from Abbott Laboratories, which developed the compound.

The agent works by manipulating members of the BCL-2 family of proteins, which includes both pro-apoptotic and anti-apoptotic molecules. (Apoptosis is a process whereby a cell kills itself because it is seriously injured or growing out of control).

ABT-737 targets the best-known member of the group, also called BCL-2, which is a cell "survival" protein that is over-expressed in many types of cancer. This protein prevents a cell from committing apoptosis by latching on to other BCL-2 family member proteins that promote cell death, thus rendering them ineffective. ABT-737, however, was engineered to fit tightly on to BCL-2, occupying that binding space so that the other pro-apoptotic proteins can function and promote cell death.

In this study, Andreeff and a team of researchers found that ABT-737 "potently" kills AML cell lines as well as blast cells taken from AML patients. "Most importantly, our results demonstrated killing of the progenitor and stem cells responsible for production of AML, which makes this a truly innovative treatment for different leukemias and cancer," Andreeff said.

However, AML cells in which another anti-apoptotic protein known as MCL-1 is over expressed did not die, which makes this protein a "resistance factor" to ABT-737 and to standard chemotherapy, he said. "In myeloid leukemia, MCL-1 can be more important than BCL-2 because when a cell has a significant amount of MCL-1, many drugs don't work," said Andreeff. In fact, he added, patients whose cells over-express MCL-1 were found by his group to have a poorer outcome.

So, the researchers added an experimental drug, a MAP-kinase inhibitor, to knock down MCL-1 expression, and found that this inhibitor also worked to inhibit cells in which BCL-2 is phosphorylated, which can switch a protein on or off. "ABT-737 had diminished effects against cells with phosphorylated BCL-2, which was restored by combination with a MAPK inhibitor," Andreeff said.

The study helps refine the understanding of the effects of ABT-737 on cancer cells, he said.

By using knock-out technology, the researchers also found that in leukemia cells, ABT-737 was dependent on two proteins called BAX and BAK to trigger apoptosis. Other researchers have said that the critical partner to ABT-737 was a similar protein known as BIM. "Both of these proteins poke holes in a cell mitochondria and release proteins that initiate cell death, but it is important to know that BAX and BAK are the important players," he said.

Andreeff said that the next step for M. D. Anderson researchers is to test ABT-737 in patients with leukemias.

Julie A. Penne | EurekAlert!
Further information:
http://www.mdanderson.org

Further reports about: ABT-737 AML Andreeff Bcl-2 Mcl-1 Protein chemotherapy leukemia

More articles from Life Sciences:

nachricht Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Future electronic components to be printed like newspapers

A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.

The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...

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....

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

Princeton-UPenn research team finds physics treasure hidden in a wallpaper pattern

20.07.2018 | Materials Sciences

Computer model predicts how fracturing metallic glass releases energy at the atomic level

20.07.2018 | Physics and Astronomy

Relax, just break it

20.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>