Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics

Abstract

The year of 2005 was a watershed in the history of poly(ADP-ribose) polymerase (PARP) inhibitors due to the important findings of selective killing in BRCA-deficient cancers by PARP inhibition. The findings made PARP inhibition one of the most promising new therapeutic approaches to cancers, especially to those with specific defects. With AZD2281 and BSI-201 entering phase III clinical trials, the final application of PARP inhibitors in clinic would come true soon. This current paper will review the major advances in targeting PARP for cancer therapy and discuss the existing questions, the answers to which may influence the future of PARP inhibitors as cancer therapeutics.

Synergistic Effect of Olaparib with Combination of Cisplatin on PTEN-Deficient Lung Cancer Cells

“…PARP inhibitor is one of the most promising new therapeutic approaches to cancers, either as a single agent or in combination with other DNA-damaging agents including radiation therapy (1). When PARP is inhibited, single-strand breaks (SSB) degenerate to more lethal double-strand breaks (DSB) that require repair by homologous recombination (HR).…”

A Quantitative Assay Reveals Ligand Specificity of the DNA Scaffold Repair Protein XRCC1 and Efficient Disassembly of Complexes of XRCC1 and the Poly(ADP-ribose) Polymerase 1 by Poly(ADP-ribose) Glycohydrolase

“…1A) (7,10,11). Pharmacological blockade of PARP1 by small molecule PARP inhibitors slows the repair of DNA single-and double-strand breaks, selectively killing tumors with genetic defects in homology-directed repair including BRCA-deficient breast cancer cells (12)(13)(14). A deficiency in PARG glycohydrolase activity prolongs DNA damage foci, containing PAR, and similarly delays DNA repair, causing hypersensitivity to DNAdamaging agents and selective killing of BRCA-deficient cancer cells in a manner similar to PARP inhibition (15,16).…”

PARP Inhibitors in Cancer Therapy: Promise, Progress, and Puzzles

“…Olaparib (AZD2281) and veliparib (ABT888) are competitive inhibitors which mimic nicotinamide and compete for the catalytic domain of PARP1 and PARP2 (He et al, 2010). In keeping with its predicted mechanism, olaparib has been tested as a single-agent in patients with advanced cancers, and significant tumor regression has been observed only in those with BRCA1/2-associated tumors (Fong et al, 2009; Tutt et al, 2010).…”

“…Further, in cell-based assays, iniparib exhibits potency in the micromolar range compared to the low nanomolar range displayed by other PARP inhibitors. Indeed, no maximally tolerated dose has been established for this agent (He et al, 2010). Thus, while iniparib represents an exciting compound from the clinical perspective, its precise mechanism of action remains to be defined.…”