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.
LLU Cancer Center Biospecimen Laboratory, Loma Linda University, Loma Linda, CA, USA; Division of Oncology & Hematology, Loma Linda University, Loma Linda, CA, USA.
Oral Oncol. 2014 Jul;50(7):662-9. doi: 10.1016/j.oraloncology.2014.03.006. Epub 2014 Apr 13.
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.
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.
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.
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.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂可能为利用细胞 DNA 修复系统缺陷选择性杀伤肿瘤细胞提供机会。我们之前证明，多受体酪氨酸激酶抑制剂贝伐单抗（ABT-869）通过抑制 STAT3 激活，可使头颈部鳞状细胞癌（HNSCC）细胞对放疗增敏。鉴于 STAT3 可以调节 DNA 损伤反应（DDR）途径，在这项研究中，我们评估贝伐单抗（ABT-888）抑制 STAT3 激活以增强 HNSCC 中细胞毒性的作用。
用贝伐单抗（ABT-869）和贝伐单抗（ABT-888）处理 UMSCC-22A 和 UMSCC-22B 细胞。通过 MTT 测定、集落形成测定、流式细胞术和彗星试验检测细胞活力、细胞毒性、细胞凋亡诱导、DNA 单链断裂（SSB）和双链断裂（DSB）损伤。此外，使用 Western 免疫印迹法评估 DNA 同源重组修复蛋白 Rad51、双链断裂标志物γH2AX 和凋亡细胞死亡标志物 cleaved PARP 的表达。
联合治疗导致细胞生长抑制、凋亡诱导、DNA 损伤和双链断裂增加，Rad51 表达降低，γH2AX 表达增加和 PARP 切割增加。
这些数据表明，联合使用贝伐单抗等靶向治疗与 veliparib 以通过合成致死性增强 HNSCC 细胞的细胞生长抑制和凋亡的可能性。因此，它可能为 HNSCC 提供一种新的治疗策略，并提高疗效和结果。
