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

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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.

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Abbreviations

ER:

Estrogen receptor

ERKs:

Extracellular signal related kinases

PAR:

Poly(ADP-ribose)

PARP:

Poly(ADP-ribose) polymerase

pCR:

Pathological complete response

PHLPP:

PH domain leucine-rich repeat phosphatase

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

TNBC:

Triple-negative breast cancer

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Acknowledgments

This study was supported by the Stefanie Spielman Fund for Breast Cancer Research and the Lucius A. Wing Endowed Chair Fund of The Ohio State University College of Medicine.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University (OSU), Columbus, OH, 43210, USA

    Hsiao-Ching Chuang, Naval Kapuriya, Samuel K. Kulp & Ching-Shih Chen

  2. Division of Medical Oncology, Wexner Medical Center and the Breast Program, OSU Comprehensive Cancer Center, Columbus, OH, 43210, USA

    Charles L. Shapiro

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  1. Hsiao-Ching Chuang
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  2. Naval Kapuriya
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  3. Samuel K. Kulp
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  4. Ching-Shih Chen
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Correspondence to Charles L. Shapiro.

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Chuang, HC., Kapuriya, N., Kulp, S.K. et al. Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells. Breast Cancer Res Treat 134, 649–659 (2012). https://doi.org/10.1007/s10549-012-2106-5

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