Small molecules overcome drug resistance in cancers associated with high-risk viruses

Treatment of human cancer is often impeded when cancer cells develop resistance to drugs that are designed to induce a type of programmed cell death called apoptosis. A new study published in the February issue of Cancer Cell identifies compounds and mechanisms that can overcome a specific type of resistance to chemotherapeutic-induced apoptosis. The findings may have application for treatment of cancers that are linked to the human papilloma virus (HPV) oncoprotein E6, such as cervical cancer.

Certain viral oncoproteins, including HPV E6, are known to interfere with the function of a protein called p53, a key tumor suppressor involved in apoptosis. Loss of p53 is linked to uncontrolled cell proliferation, the hallmark of cancer, and is known to increase the resistance of tumor cells to some chemotherapeutic treatments. HPV is a major cause of cervical cancer, and earlier studies have suggested that interfering with E6 may lead to the death of E6-expressing cells. However, methods used to target E6 in these studies involved techniques that are not easily translatable to therapeutic use, and at this time, no specific therapies exist.

Dr. Brent R. Stockwell and colleagues from Columbia University designed a study to uncover small molecules that can overcome E6-induced drug resistance and which would be more easily adaptable to cancer treatment. The researchers used a screening method to look for compounds that potentiate chemotherapeutic effectiveness of the agent doxorubicin in E6-expressing colon cancer cells that are normally relatively resistant to the drug. "We identified several groups of compounds that potentiate doxorubicin's lethality in E6-expressing tumor cells, thus overcoming E6-induced drug resistance," offers Dr. Stockwell.

Results describe one group of compounds, named indoxins, that proved to be dual-action agents that drive two distinct cell cycle-related mechanisms. Dr. Stockwell explains that activation of each mechanism alone had only a modest effect on chemotherapeutic effectiveness, but activation of both mechanisms simultaneously contributed substantially to doxorubicin sensitivity. Enhanced understanding of the mechanisms that are associated with doxorubicin resistance will lead to design of future therapies that can be specifically targeted to overcome drug resistance in E6-expressing tumors.

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The researchers included Inese Smukste, Oneil Bhalala, Marco Persico, and Brent R. Stockwell of Columbia University in New York, NY. B.R.S. is supported by a Career Award at the Scientific Interface from the Burroughs Welcome Fund and by the National Cancer Institute (R01 CA097061). M.P. was funded in part by the SURF undergraduate fellowship from the Columbia University. O.B. was in part supported by the UROP undergraduate research fellowship from MIT.

Smukste et al.: "Using small molecules to overcome drug resistance induced by a viral oncogene." Publishing in Cancer Cell 9, 133146, February 2006. DOI 10.1016/j.ccr.2006.01.012 www.cancercell.org


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