Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells

Breast Cancer Res Treat. 2012 Jul;134(2):649-59. doi: 10.1007/s10549-012-2106-5. Epub 2012 Jun 8.

Abstract

Despite recent advances in the clinical evaluation of various poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer (TNBC) patients, data defining potential anti-tumor mechanisms beyond PARP inhibition for these agents are lacking. To address this issue, we investigated the effects of four different PARP inhibitors (AG-014699, AZD-2281, ABT-888, and BSI-201) in three genetically distinct TNBC cell lines (MDA-MB-468, MDA-MB-231, and Cal-51). Assays of cell viability and colony formation and flow cytometric analysis were used to determine effects on cell growth and cell cycle progression. PARP-dependent and -independent signaling mechanisms of each PARP inhibitor were investigated by western blotting and shRNA approaches. Potential synergistic interactions between PARP inhibitors and cisplatin in suppressing TNBC cell viability were assessed. These PARP inhibitors exhibited differential anti-tumor activities, with the relative potencies of AG-014699 > AZD-2281 > ABT-888 > BSI-201. The higher potencies of AG-014699 and AZD-2281 were associated with their effects on G(2)/M arrest and DNA damage as manifested by γ-H2AX formation and, for AG-014699, its unique ability to suppress Stat3 phosphorylation. Abilities of individual PARP inhibitors to sensitize TNBC cells to cisplatin varied to a great extent in a cell context- and cell line-specific manner. Differential activation of signaling pathways suggests that the PARP inhibitors currently in clinical trials have different anti-tumor mechanisms beyond PARP inhibition and these PARP-independent mechanisms warrant further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • Benzamides / pharmacology*
  • Benzimidazoles / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Cell Line, Tumor / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Down-Regulation / drug effects
  • Drug Synergism
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Phthalazines / pharmacology*
  • Piperazines / pharmacology*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • RNA Interference
  • Receptor, ErbB-2 / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • BRCA1 Protein
  • BRCA1 protein, human
  • Benzamides
  • Benzimidazoles
  • Indoles
  • Intercellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Receptors, Estrogen
  • Receptors, Progesterone
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • veliparib
  • iniparib
  • rucaparib
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • PHLPP1 protein, human
  • Phosphoprotein Phosphatases
  • Cisplatin
  • olaparib