NIH study uncovers new mechanism of action for class of chemotherapy drugs
National Institutes of Health (NIH) researchers have discovered a significant new mechanism of action for a class of chemotherapy drugs known as poly (ADP-ribose) polymerase inhibitors, or PARP inhibitors. They have also identified differences in the toxic capabilities of three drugs in this class which are currently being tested in clinical trials. The study, by scientists at the National Cancer Institute (NCI), part of NIH, and their colleagues, appeared in Cancer Research, Nov 1, 2012.
In recent years, drugs classified as PARP inhibitors have been shown to be promising anticancer agents for breast and ovarian cancer. Members of the PARP family of proteins are involved in a number of critical cellular processes, including DNA damage repair and programmed cell death. Prior to this study, PARP inhibitors were thought to work primarily by blocking PARP enzyme activity, thus preventing the repair of DNA damage and ultimately causing cell death.
In this study, scientists established that PARP inhibitors have an additional mode of action: localizing PARP proteins at sites of DNA damage, which has relevance to their anti-tumor activity. The trapped PARP protein–DNA complexes are highly toxic to cells because they block DNA replication. When the researchers tested three PARP inhibitors for their differential ability to trap PARP proteins on damaged DNA, they found that the trapping potency of the inhibitors varied widely.
“Critical to our research is that, while PARP inhibitors had been assumed to be of equivalent potency based on the degree to which they elicit PARP inhibition, we now know that they are not equivalent with respect to their potency to trap PARP,” said Yves Pommier, M.D., Ph.D., NCI Center for Cancer Research. “Our findings suggest that PARP inhibitors should be categorized according to their potency to trap PARP, in addition to their enzyme inhibition abilities.”
The PARP family of proteins in humans includes PARP1 and PARP2, which are DNA binding and repair proteins. When activated by DNA damage, these proteins recruit other proteins that do the actual work of repairing DNA. Under normal conditions, PARP1 and PARP2 are released from DNA once the repair process is underway. However, as this study shows, when they are bound to PARP inhibitors, PARP1 and PARP2 become trapped on DNA. The researchers showed that trapped PARP–DNA complexes are more toxic to cells than the unrepaired single-strand DNA breaks that accumulate in the absence of PARP activity, indicating that PARP inhibitors act as PARP poisons.
In collaboration with James Doroshow, M.D., deputy director for clinical and translational research at NCI, the investigators used PARP assays (ways of measuring PARP activity in cells and tissues) to compare three PARP inhibitor compounds that are currently in clinical testing: MK-4827, olaparib, and veliparib.
The scientists found that the three PARP inhibitors differed in their ability to inhibit PARP enzyme activity, with olaparib being the most potent inhibitor, followed by veliparib and then MK-4827. However, in terms of toxicity, MK-4827 was the most potent, followed by olaparib and then veliparib. Moreover, PARP1 complexes with MK-4827 and olaparib were shown to be more tightly bound to DNA than complexes with veliparib.
These findings suggest that there may be two classes of PARP inhibitors, catalytic inhibitors that act mainly to inhibit PARP enzyme activity and do not trap PARP proteins on DNA, and dual inhibitors that both block PARP enzyme activity and act as PARP poison.
“Our findings suggest that clinicians who use PARP inhibitors in clinical trials should carefully choose their drug, because we now suspect results may differ, depending upon the PARP inhibitor used,” said Junko Murai, M.D., Ph.D., NCI Center for Cancer Research. “As a next step, we are working to categorize other leading PARP inhibitors based upon both PARP trapping and PARP inhibition.”
This work was supported by the Intramural Program of NCI and by the Japan Society for the Promotion of Science (JSPS) Core-to-Core Program. First author Junko Murai is a JSPS fellow working at NCI Center for Cancer Research. Funding was provided by NCI grant Z01 BC 006150-19LMP.
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Reference: Murai J, et al. Differential trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Research. Nov 1, 2012.