title: The PARP inhibitor ABT-888 potentiates dacarbazine-induced cell death in carcinoids.
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/Cip1activation, 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.
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Somnay
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lubner
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Gill
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Matsumura
authors.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Surgery, University of Alabama- Birmingham, Birmingham, AL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chen
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D003606:Dacarbazine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D009362:Neoplasm Metastasis; D010641:Phenotype; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003606:Dacarbazine