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

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 G2/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.

Comparative antiproliferative effects of iniparib and olaparib on a panel of triple-negative and non-triple-negative breast cancer cell lines

“…Our results are thus consistent with recent studies showing that iniparib was a weak inhibitor of PARP1. [20][21][22] Although MTT and colony formation assays are widely used to evaluate in vitro antiproliferative activities of investigational drugs, we showed that the IC 50 values obtained with the colony formation assay were consistently lower than those obtained with the MTT assays. Furthermore, no significant correlation was found between the IC 50 values obtained with the two assays across the panel cell lines investigated.…”

Rationale for Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Combination Therapy with Camptothecins or Temozolomide Based on PARP Trapping versus Catalytic Inhibition

“…Enhanced effects of PARP inhibitors with cisplatin have been reported (Rottenberg et al, 2008;Hastak et al, 2010;Chuang et al, 2012). However, the synergistic effects in these studies are relatively weak compared with those in the reports dealing with temozolomide (Brenner et al, 2012;Kedar et al, 2012;Horton and Wilson, 2013) and camptothecin (Smith et al, 2005;Daniel et al, 2009;Zhang et al, 2011).…”

Poly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma

“…[21][22][23]. PARP inhibitors are synthetically lethal in BRCA1/2-mutated tumors with DNA repair deficiencies and have been shown to be effective when combined with DNAdamaging agents in isogenic BRCA1/2-deleted cell lines and BRCA1-deficient mouse models (24)(25)(26)(27).…”

“…This led us to hypothesize that PARP inhibition could potentially be used as a monotherapy or to enhance the therapeutic index of ionizing radiation (IR) in pHGA and DIPG. Veliparib, olaparib, and niraparib are three orally available PARP inhibitors which have all entered phase III clinical trials for adult cancer, demonstrating good tolerability in phase II studies (25)(26)(27)(28)(29)(30)(31). However, there is a lack of knowledge regarding the efficacy of these PARP inhibitors in pediatric brain tumors.…”