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Linifanib (ABT-869), enhances cytotoxicity with poly (ADP-ribose) polymerase inhibitor, veliparib (ABT-888), in head and neck carcinoma cells
- Source :
- Oral oncology. 50(7)
- Publication Year :
- 2014
-
Abstract
- Summary Objectives 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. Materials and 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. Conclusion 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.
- Subjects :
- Cancer Research
Indazoles
Veliparib
DNA damage
Cell Survival
Poly ADP ribose polymerase
Apoptosis
Biology
Poly(ADP-ribose) Polymerase Inhibitors
Poly (ADP-Ribose) Polymerase Inhibitor
Histones
chemistry.chemical_compound
Cell Line, Tumor
medicine
Humans
Phenylurea Compounds
DNA Breaks
medicine.disease
Head and neck squamous-cell carcinoma
Molecular biology
Comet assay
Linifanib
Oncology
chemistry
Head and Neck Neoplasms
PARP inhibitor
Cancer research
Carcinoma, Squamous Cell
Benzimidazoles
Rad51 Recombinase
Oral Surgery
Poly(ADP-ribose) Polymerases
Subjects
Details
- ISSN :
- 18790593
- Volume :
- 50
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Oral oncology
- Accession number :
- edsair.doi.dedup.....3faebf4deac3ed2a909b0b4daef09383