PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation

Ahrum Min; Seock-Ah Im

doi:10.3390/cancers12020394

PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation

Cancers (Basel). 2020 Feb 8;12(2):394. doi: 10.3390/cancers12020394.

Authors

Ahrum Min^{1

2}, Seock-Ah Im^{1

2

3

4}

Affiliations

¹ Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
² Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea.
³ Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea.
⁴ Translational Medicine, Seoul National University College of Medicine, Seoul 03080, Korea.

Abstract

Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively binding to NAD+ binding site of PARP1 and PARP2, have improved clinical benefits for BRCA mutated tumors, leading to their accelerated clinical application. However, the antitumor activities of PARP inhibitors in clinical development are different, due to PARP trapping activity beyond blocking PARylation reactions. In this review, we comprehensively address the current state of knowledge regarding the mechanisms of action of PARP inhibitors. We will also discuss the different effects of PARP inhibitors in combination with cytotoxic chemotherapeutic agents regarding the mechanism of regulating PARylation.

Keywords: PARP; PARP inhibitors; PARylation; cancer therapeutic strategy; trapping.

Publication types

Review