How to kill tumor cells with inhibitors of poly(ADP-ribosyl)ation

Abstract

Poly(ADP-ribosyl)ation is a post-translational modification catalyzed by the enzyme family of poly(ADP-ribose) polymerases (PARPs). PARPs exhibit pleiotropic cellular functions ranging from maintenance of genomic stability and chromatin remodeling to regulation of cell death, thereby rendering PARP homologues promising targets in cancer therapy. Depending on the molecular status of a cancer cell, low-molecular weight PARP inhibitors can (i) either be used as monotherapeutic agents following the concept of synthetic lethality or (ii) to support classical chemotherapy or radiotherapy. The rationales are the following: (i) in cancers with selective defects in homologous recombination repair, inactivation of PARPs directly causes cell death. In cancer treatment, this phenomenon can be employed to specifically target tumor cells while sparing nonmalignant tissue. (ii) PARP inhibitors can also be used to sensitize cells to cytotoxic DNA-damaging treatments, as some PARPs actively participate in genomic maintenance. Apart from that, PARP inhibitors possess antiangiogenic functions, thus opening up a further option to inhibit tumor growth. In view of the above, a number of high-potency PARP inhibitors have been developed during the last decade and are currently evaluated as cancer therapeutics in clinical trials by several leading pharmaceutical companies.