Poly (ADP-ribose) polymerase (PARP) inhibitors as chemosensitizing compounds for the treatment of drug resistant cancers

Abstract

Poly (ADP-ribose) polymerase (PARP) proteins mediate various cellular processes such as DNA repair, regulation of transcription, protein-protein interaction, expression of inflammatory genes and programmed cell death. PARP proteins have a key role in DNA repair and recent findings have established the role of PARP inhibitors as potent chemotherapeutic drugs. Among the 18 members, PARP1 and PARP2 have been identified as the main targets for the development of pharmacological inhibitors to enhance the cytotoxic efficacy of established anticancer drugs. Furthermore, certain PARP1 and PARP2 inhibitors are being used in combination with other drugs for the treatment of various types of cancer. In different drug resistant cancer cell types, PARP inhibitors have been identified as compounds that reverse the resistance to topoisomerase inhibitors, DNA alkylating and methylating drugs by enhancing the DNA damage induced by these agents. In BRCA mutant cells, with abnormal homologous recombination (HR) repair mechanism, BER (Base Excision Repair Pathway) is responsible for survival of the cells. PARP enzymes play a major role in BER and PARP inhibitors effectively target BRCA mutant cells sparing normal cells via the concept of synthetic lethality, producing minimal toxicity to PARP inhibitors also have a significant role in treating pancreatic adenocarcinoma and castration-resistant prostate cancer. The aim of the current paper is to provide a review on PARP inhibitors and their application in the treatment of various cancer cells which are resistant to standard chemotherapeutic drugs.