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The PARP inhibitor ABT-888 potentiates dacarbazine-induced cell death in carcinoids

Cancer Gene Therapy volume 23, pages 348–354 (2016)Cite this article

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Abstract

Monoagent DNA-alkylating chemotherapies like dacarbazine are among a paucity of medical treatments for advanced carcinoid tumors, but are limited by host toxicity and intrinsic chemoresistance through the base excision repair (BER) pathway via poly (ADP-ribose) polymerase (PARP). Hence, inhibitors of PARP may potentiate DNA-damaging agents by blocking BER and DNA restoration. We show that the PARP inhibitor ABT-888 (Veliparib) enhances the cytotoxic effects of dacarbazine in carcinoids. Two human carcinoid cell lines (BON and H727) treated with a combination of ABT-888 and dacarbazine resulted in synergistic growth inhibition signified by combination indices <1 on the Chou-Talalay scale. ABT-888 administered prior to varying dacarbazine doses promoted the suppression of neuroendocrine biomarkers of malignancy, ASCL1 and chromogranin A, as shown by western analysis. Ataxia telangiectasia mitogen factor phosphorylation and p21Waf1/Cip1 activation, indicative of DNA damage, were increased by ABT-888 when combined with dacarbazine treatment, suggesting BER pathway attenuation by ABT-888. PE Annexin V/7-AAD staining and sorting revealed a profound induction of apoptosis following combination treatment, which was further confirmed by increased PARP cleavage. These results demonstrate that ABT-888 synergizes dacarbazine treatment in carcinoids. Therefore, ABT-888 may help treat carcinoids unresponsive or refractory to mainstay therapies.

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Acknowledgements

Funding was provided by (1) NIH National Research Service Award T32 GM07215 (YS), (2) American Cancer Society MEN2 Thyroid Cancer Professorship 120319-RPM-11-080-01-TBG (HC), (3) American Cancer Society Research Scholar Award RSGM TBE-121413 (HC) and (4) Caring for Carcinoid Foundation Grant from the American Association for Cancer Research (HC).

Author contributions

YS executed all the experiments with assistance from Harpreet Gill and Jon Blake Matsumura. Drs Sam Lubner and Herbert Chen guided the project’s trajectory and interpretation of findings.

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Authors and Affiliations

  1. Department of Surgery, Endocrine Surgery Research Laboratories, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Y Somnay, H Gill, J B Matsumura & H Chen

  2. Division of Hematology and Medical Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    S Lubner

  3. Department of Surgery, University of Alabama- Birmingham, Birmingham, AL, USA

    H Chen

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Correspondence to H Chen.

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Somnay, Y., Lubner, S., Gill, H. et al. The PARP inhibitor ABT-888 potentiates dacarbazine-induced cell death in carcinoids. Cancer Gene Ther 23, 348–354 (2016). https://doi.org/10.1038/cgt.2016.39

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