Department of Pharmacology, Loma Linda University, Loma Linda, CA, USA.
Oral Oncol. 2013 Jun;49(6):591-7. doi: 10.1016/j.oraloncology.2013.02.009. Epub 2013 Mar 13.
Novel targeted therapeutic strategies to overcome radio-resistance of cancer cells traditionally treated with radiation may improve patient survival with the added benefit of reduced systemic toxicity. Herein, we tested the feasibility of Linifanib (ABT-869), a multi-receptor tyrosine kinase inhibitor of members of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor families, on radio-sensitization of Head and Neck Squamous Cell Carcinoma (HNSCC).
UMSCC-22A and UMSCC-22B cells were treated with Linifanib and γ-radiation response was determined. Cell viability, cytotoxicity, apoptosis induction and cell cycle distribution were examined by MTT assay, colony formation assay and flow cytometry. In addition, expression of STAT3 and downstream signaling proteins were assessed using western immunoblotting.
Treatment with Linifanib resulted in cell growth inhibition, G2/M cell cycle arrest, induction of cell death via apoptosis, reduced phosphorylation of STAT3, which has been linked to radio-resistance, lower expression of cyclin D1, survivin and increased PARP cleavage. In addition, Linifanib overcame the radio-resistance of the cell lines and significantly enhanced radiation-induced cytotoxicity (p<0.05).
These data suggest the possibility of combining targeted therapeutic such as Linifanib with radiation to enhance inhibition of cell growth and apoptosis in HNSCC cells. Thus, it may provide a novel therapeutic strategy and improve efficacy of radiation against HNSCC in the future.
为克服传统放疗的癌细胞放射抵抗，研发新型靶向治疗策略可能提高患者生存率，并降低全身毒性。在此，我们测试了 Linifanib（ABT-869）在头颈部鳞状细胞癌（HNSCC）放射增敏中的可行性，Linifanib 是血管内皮生长因子（VEGF）和血小板衍生生长因子（PDGF）受体家族成员的多受体酪氨酸激酶抑制剂。
用 Linifanib 处理 UMSCC-22A 和 UMSCC-22B 细胞，并检测其对放射的反应。通过 MTT 测定、集落形成测定和流式细胞术检测细胞活力、细胞毒性、细胞凋亡诱导和细胞周期分布。此外，通过 Western 免疫印迹法评估 STAT3 及其下游信号蛋白的表达。
Linifanib 治疗导致细胞生长抑制、G2/M 细胞周期阻滞、通过凋亡诱导细胞死亡、降低与放射抵抗相关的 STAT3 磷酸化、下调 cyclin D1、survivin 的表达和增加 PARP 裂解。此外，Linifanib 克服了细胞系的放射抵抗，并显著增强了辐射诱导的细胞毒性（p<0.05）。
这些数据表明，将靶向治疗（如 Linifanib）与放疗相结合以增强 HNSCC 细胞生长抑制和凋亡的可能性。因此，它可能为未来提供一种新的治疗策略，并提高放疗对 HNSCC 的疗效。
