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

Y Somnay1, S Lubner2, H Gill1

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

Cancer Gene Therapy
|September 17, 2016
PubMed

Insights

Poly (ADP-ribose) polymerase (PARP) inhibitors like ABT-888 (Veliparib) can enhance chemotherapy for carcinoid tumors. Combining ABT-888 with dacarbazine synergistically inhibits tumor growth and induces apoptosis, offering a new treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Advanced carcinoid tumors have limited treatment options, with DNA-alkylating agents like dacarbazine being restricted by toxicity and chemoresistance.
  • The base excision repair (BER) pathway, mediated by poly (ADP-ribose) polymerase (PARP), contributes to chemoresistance by repairing DNA damage.
  • PARP inhibitors are being investigated to overcome chemoresistance by blocking DNA repair mechanisms.

Purpose of the Study:

  • To investigate the potential of the PARP inhibitor ABT-888 (Veliparib) to enhance the efficacy of dacarbazine in treating carcinoid tumors.
  • To determine if combining ABT-888 with dacarbazine leads to synergistic cytotoxic effects and overcomes chemoresistance.

Main Methods:

  • Two human carcinoid cell lines (BON and H727) were treated with dacarbazine alone and in combination with ABT-888.
  • Synergistic growth inhibition was assessed using the Chou-Talalay method.
  • Western analysis was used to evaluate the suppression of neuroendocrine biomarkers (ASCL1, chromogranin A) and DNA damage markers (phosphorylated ataxia telangiectasia mutated, p21Waf1/Cip1).
  • Apoptosis was quantified using PE Annexin V/7-AAD staining and confirmed by assessing PARP cleavage.

Main Results:

  • The combination of ABT-888 and dacarbazine demonstrated synergistic growth inhibition in carcinoid cell lines (Combination Index <1).
  • ABT-888 treatment prior to dacarbazine suppressed key neuroendocrine biomarkers and increased markers of DNA damage, indicating BER pathway inhibition.
  • Combination therapy significantly induced apoptosis, evidenced by increased PARP cleavage.

Conclusions:

  • ABT-888 (Veliparib) synergizes with dacarbazine, enhancing its cytotoxic effects in carcinoid tumors.
  • This combination therapy shows promise for treating carcinoid tumors that are unresponsive or refractory to conventional therapies.
  • Targeting the BER pathway with PARP inhibitors may represent a viable strategy to improve outcomes for patients with advanced carcinoid tumors.

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