title: Linifanib (ABT-869), enhances cytotoxicity with poly (ADP-ribose) polymerase inhibitor, veliparib (ABT-888), in head and neck carcinoma cells.
abstract: OBJECTIVE
  PARP inhibitors (PARPi) may provide an opportunity to gain selective killing of tumor cells which have deficiencies in cellular DNA repair systems. We previously demonstrated linifanib (ABT-869), a multi-receptor tyrosine kinase inhibitor of VEGF and PDGF receptor families, radiosensitized Head and Neck Squamous Cell Carcinoma cells (HNSCC) via inhibiting STAT3 activation. Given that STAT3 can modulate DNA damage response (DDR) pathway, in this study, we evaluate the effects of linifanib to enhance cytotoxicity with the PARPi, veliparib (ABT-888), in HNSCC.
  
  
  METHODS
  UMSCC-22A and UMSCC-22B cells were treated with linifanib (ABT-869) and veliparib (ABT-888). Cell viability, cytotoxicity, apoptosis induction, DNA single strand break (SSB) and double strand break (DSB) damages were examined by MTT assay, colony formation assay, flow cytometry and comet assay. In addition, the expression of DNA homologous recombination repair protein Rad51, γH2AX, a double strand break marker and cleaved PARP, an apoptotic cell death marker, were assessed using western immunoblotting.
  
  
  RESULTS
  Combination treatment resulted in more cell growth inhibition, induction of apoptosis, DNA damages and double strand breaks, lower expression of Rad51, increase γH2AX expression and PARP cleavage.
  
  
  CONCLUSIONS
  These data suggest the possibility of combining targeted therapeutic such as linifanib with veliparib to augment the inhibition of cell growth and apoptosis via synthetic lethality in HNSCC cells. Thus, it may provide a novel therapeutic strategy and improve efficacy and outcome in HNSCC.
authors.affiliation: Department of Pharmacology, Loma Linda University, Loma Linda, CA, USA; Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA; LLU Cancer Center Biospecimen Laboratory, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Heng-Wei
authors.initials: HW
authors.lastname: Hsu
authors.affiliation: LLU Cancer Center Biospecimen Laboratory, Loma Linda University, Loma Linda, CA, USA; Division of Oncology & Hematology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Rosalia
authors.initials: R
authors.lastname: de Necochea-Campion
authors.affiliation: Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Vonetta
authors.initials: V
authors.lastname: Williams
authors.affiliation: Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Duerksen-Hughes
authors.affiliation: Department of Otolaryngology and Head/Neck Surgery, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Simental
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA, USA; LLU Cancer Center Biospecimen Laboratory, Loma Linda University, Loma Linda, CA, USA; Division of Oncology & Hematology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA, USA; Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA; LLU Cancer Center Biospecimen Laboratory, Loma Linda University, Loma Linda, CA, USA. Electronic address: smirshahidi@llu.edu.
authors.forename: Saied
authors.initials: S
authors.lastname: Mirshahidi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053960:DNA Breaks / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; C468783:H2AX protein, human; D006657:Histones; D007191:Indazoles; D010671:Phenylurea Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; C513486:linifanib; D011065:Poly(ADP-ribose) Polymerases; D051135:Rad51 Recombinase
keywords: Apoptosis; DNA damage; Head and Neck Squamous Cell Carcinoma; Homologous recombination repair; Linifanib (ABT-869); PARP inhibitor; Veliparib (ABT-888)