PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors

Int J Mol Sci. 2020 Nov 5;21(21):8288. doi: 10.3390/ijms21218288.

Abstract

Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes' assembly. Nuclear PAR affects chromatin's structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1/2), base excision repair proteins (XRCC1, Polβ), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested.

Keywords: CDKN2A; KU-0060648; KU55933; Olaparib; PARP-1; SCR7 pyrazine; VERO cells; poly(ADP-ribosylation); resistance; synergism.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
  • Bleomycin / pharmacology*
  • Chlorocebus aethiops
  • Chromones / pharmacology*
  • DNA Ligase ATP / antagonists & inhibitors
  • DNA Repair / drug effects
  • DNA-Activated Protein Kinase / antagonists & inhibitors
  • Drug Combinations
  • Drug Resistance, Neoplasm / drug effects
  • Drug Synergism
  • Morpholines / pharmacology*
  • Phthalazines / pharmacology*
  • Piperazines / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Pyrimidines / pharmacology*
  • Pyrones / pharmacology*
  • Schiff Bases / pharmacology*
  • Thiophenes / pharmacology*
  • Vero Cells

Substances

  • 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo(b,d)thiophen-1-yl)acetamide
  • 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
  • 5,6-bis(benzylideneamino)-2-mercaptopyrimidin-4-ol
  • Antineoplastic Agents
  • Chromones
  • Drug Combinations
  • Morpholines
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Pyrimidines
  • Pyrones
  • Schiff Bases
  • Thiophenes
  • Bleomycin
  • Ataxia Telangiectasia Mutated Proteins
  • DNA-Activated Protein Kinase
  • DNA Ligase ATP
  • olaparib