2-Methoxy antimycin, Bcl-2 inhibitor

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Cell Toxin Found To Inhibit Survival Proteins In Cancer Cells Has New

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Main Category: Cancer / Oncology News

Article Date: 15 Jul 2007 - 11:00 PDT

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A chemically-modified version of a mitochondrial toxin long used to

control species of invasive fish in lakes has been found to

selectively inhibit two " survival proteins " in cancer cells. The

research is a first step toward developing a molecularly-targeted

drug that could eliminate cellular-level resistance to multiple types

of chemotherapy and radiation therapy found in many types of cancers.

In a paper published in the July 2007 issue of Molecular Cancer

Therapeutics, scientists at Fred Hutchinson Cancer Research Center

report that a modified version of antimycin called 2-Methoxy

antimycin is selective in killing cells that have high levels of Bcl-

2 and Bcl-xL proteins. The over expression of these proteins in many

types of cancer cells correlates with resistance to chemotherapy and

radiation therapy. Cells with normal levels of Bcl-2 or Bcl-xL are

resistant to 2-Methoxy antimycin.

M. Hockenbery, a member of the Hutchinson Center's Clinical

Research Division and principal investigator for the study, and

colleagues set up screening assays to look for small molecules or

compounds that are selectively toxic to cells that over express Bcl-2

proteins. Higher expression of the target protein made cells more

sensitive to the 2-Methoxy antimycin inhibitor. This is called

a 'gain of function' mechanism and is counterintuitive to the way

most drugs work.

" Our compound, 2-Methoxy antimycin, is the only Bcl-2 inhibitor

reported with 'gain of function' activity, which provides a

therapeutic window between cancer cells with high expression of the

proteins versus cells with normal expression, " said Hockenbery, who

is also a professor of medicine at the University of Washington

Medical Center. " This effect was preserved when 2-Methoxy antimycin

was used in combination with other agents, and could lead to a

targeted molecular therapy to enhance the effectiveness of cancer

treatments. "

Hockenbery said his group's approach illustrated the need to look at

how the proteins interact with everything else in the cell. " By over

expressing this protein, the cell is changed in some interesting

ways. It creates a situation where the cell becomes dependent upon

the protein, " he said. " Cancers can become addicted to certain

proteins, so just by over expressing the protein the cell changes so

that it can't live without that protein. "

The next step in this research is to use the assays his lab developed

to 'cast a wider net' to find additional compounds that have similar

properties to 2-Methoxy antimycin, Hockenbery said. This strategy has

already yielded one additional Bcl-xL inhibitor with 'gain of

function' activity, reported in the Molecular Cancer Therapeutics

paper. Funding for the study, " 2-Methoxy antimycin reveals a unique

mechanism for Bcl-xL inhibition, " came from the New Technology

Development Fund administered by the Hutchinson Center. Additional

key investigators in Hockenbery's lab included Manion, Ph.D.,

and Pam Schwartz, Ph.D., and Fry.

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Article adapted by Medical News Today from original press release.

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Conflict of interest statement: Hockenbery is a founder of a private

company that has licensed patents held by the Hutchinson Center for

the new use 2-Methoxy antimycin, as well as the assays used to make

the discovery.

At Fred Hutchinson Cancer Research Center, our interdisciplinary

teams of world-renowned scientists and humanitarians work together to

prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our

researchers, including three Nobel laureates, bring a relentless

pursuit and passion for health, knowledge and hope to their work and

to the world. For more information, please visit

http://www.fhcrc.org/.

Source: Dean Forbes

Fred Hutchinson Cancer Research Center