A chemically modified version of a mitochondrial toxin long used to control species of invasive fish in lakes also selectively inhibits 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, Hutchinson Center scientists 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.
The Clinical Research Division's Dr. David Hockenbery 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 "gain of function" mechanism 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 pr cellsut that protein."
Time to cast wider net
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 came from the New Technology Development Fund administered by the Hutchinson Center. Additional key investigators in Hockenbery's lab included Dr. Michael Manion, Dr. Pam Schwartz and John Fry.