PARP-1 inhibitors effective against some cancers

By Aline McKenzie / Holidays 2010 

Drugs that inhibit an enzyme called PARP-1 have been shown to be effective in fighting some cancers, but why this approach works has not been fully understood.

A recent UT Southwestern study published in Molecular Cell helps explain why, and the findings could be important in developing better and more specific PARP inhibitors.

Dr. W. Lee Kraus

“Much of the focus has been on PARP-1’s role in DNA damage detection and repair,” said Dr. W. Lee Kraus, director of the Cecil H. and Ida Green Center for Reproductive Biology Sciences and senior author of the study.

“We focused on its action in gene regulation, which has added another layer of understanding to the complex set of roles that PARP-1 plays in cells. It is likely, however, that there are some functional connections between PARP-1’s roles in DNA repair and in gene regulation.”

Dr. Kraus, who also serves as vice chairman for basic science in obstetrics and gynecology, said understanding that there are multiple processes affected could aid in the development of improved PARP inhibitors.

Using cultured human breast cancer cells, Dr. Kraus and lead author Dr. Raga Krishnakumar from Cornell University focused on the interaction between PARP-1 and the histone-modifying enzyme KDM5b, which is overexpressed in many breast cancers. PARP-1 and KDM5b bind together at about one-third of all human genes. The study revealed that inhibition of PARP-1 triggers a cascade of biochemical reactions involving KDM5b that ends with repression of several cancer-related genes.

Several PARP-1 inhibitors are in clinical tests for treating certain cancers, including breast cancer, said Dr. Kraus, who also serves as vice chairman for basic science in obstetrics and gynecology.

“PARP-1 inhibition does not appear to be detrimental to normal noncancerous cells, so PARP inhibitors have the potential to impair the growth of cancer cells without damaging normal cells,” he said.

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Dr. Kraus holds the Cecil H. and Ida Green Distinguished Chair in Reproductive Biology Sciences.