title: Poly (ADP) ribose polymerase enzyme inhibitor, veliparib, potentiates chemotherapy and radiation in vitro and in vivo in small cell lung cancer.
abstract: Poly (ADP) ribose polymerase (PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer (SCLC). We investigated the therapeutic impact of PARP inhibition in SCLC. In vitro cytotoxicity of veliparib, cisplatin, carboplatin, and etoposide singly and combined was determined by MTS in 9 SCLC cell lines (H69, H128, H146, H526, H187, H209, DMS53, DMS153, and DMS114). Subcutaneous xenografts in athymic nu/nu mice of H146 and H128 cells with relatively high and low platinum sensitivity, respectively, were employed for in vivo testing. Mechanisms of differential sensitivity of SCLC cell lines to PARP inhibition were investigated by comparing protein and gene expression profiles of the platinum sensitive and the less sensitive cell lines. Veliparib showed limited single-agent cytotoxicity but selectively potentiated (≥ 50% reduction in IC50 ) cisplatin, carboplatin, and etoposide in vitro in five of nine SCLC cell lines. Veliparib with cisplatin or etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128 xenografts. The potentiating effect of veliparib was associated with in vitro cell line sensitivity to cisplatin (CC = 0.672; P = 0.048) and DNA-PKcs protein modulation. Gene expression profiling identified differential expression of a 5-gene panel (GLS, UBEC2, HACL1, MSI2, and LOC100129585) in cell lines with relatively greater sensitivity to platinum and veliparib combination. Veliparib potentiates standard cytotoxic agents against SCLC in a cell-specific manner. This potentiation correlates with platinum sensitivity, DNA-PKcs expression and a 5-gene expression profile.
authors.affiliation: Department of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta, Georgia; Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.forename: Guojing
authors.initials: G
authors.lastname: Zhang
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rossi
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Switchenko
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Doho
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.forename: Sungjin
authors.initials: S
authors.lastname: Kim
authors.forename: Sandy
authors.initials: S
authors.lastname: Strychor
authors.forename: Susan M
authors.initials: SM
authors.lastname: Christner
authors.forename: Jan
authors.initials: J
authors.lastname: Beumer
authors.forename: Chunyang
authors.initials: C
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Yue
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Sica
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kowalski
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011897:Random Allocation; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D005047:Etoposide; D016190:Carboplatin; D002945:Cisplatin
keywords: Carboplatin; PARP; SCLC; cisplatin; etoposide; veliparib (ABT-888)