Liu Ningbo, Tao Zhen, Blanc Justin M Le, Zaorsky Nicholas G, Sun Yunguang, Vuagniaux Grégoire, Dicker Adam P, Lu Bo
Department of Radiation Oncology, Tianjin Medical University Cancer Hospital Tianjin, China ; Department of Radiation Oncology, Thomas Jefferson University Philadelphia, PA, USA.
Department of Radiation Oncology, Thomas Jefferson University Philadelphia, PA, USA.
Am J Cancer Res. 2014 Nov 19;4(6):943-51. eCollection 2014.
Inhibitors of apoptosis (IAPs) limit the effectiveness of radiation in non-small cell lung cancer (NSCLC). Debio 1143 (D1143) is an antagonist of IAPs. The purpose of this study was to investigate the potential of D1143 as a radiosensitizer in NSCLC. MTS assays were performed in two NSCLC cell lines: HCC193 and H460. Extent of apoptotic cell death was characterized by Annexin V assay and Western blot for cleaved caspase-3, -8, and IAPs. TNF-α release was determined by ELISA. Radiosensitivities were compared with dose enhancement ratios (DERs). HCC193 cells D1143 IC50 was 1 μM. HCC193 cells demonstrated noticeable cleaved caspase-3, -8, and a decrease in IAP levels with 2.5 μM D1143; H460 cells, with 10 μM; both in a time-dependent manner. Additionally, HCC193 cells exhibited an increase in TNF-α. D1143 radiosensitized cells: HCC193, 2.5 μM D1143, 24 h incubation, DER of 2.19, p = 0.001; H460 cells, 10 μM D1143, 48 h incubation, DER of 1.29, p = 0.082. Treatment of H460 cells with radiation therapy, TNF-α, and D1143 further radiosensitized the cells (DER of 1.92, p = 0.026). D1143 significantly enhanced the radiosensitization of HCC193 and H460 cells in vitro. TNF-α contributed to the sensitization in the more sensitive cell line (HCC193). More research is warranted to test the mechanism of D1143, and to assess its potential in vivo in the clinical setting.
凋亡抑制蛋白（IAPs）会限制非小细胞肺癌（NSCLC）放疗的效果。Debio 1143（D1143）是一种IAPs拮抗剂。本研究的目的是探究D1143作为NSCLC放疗增敏剂的潜力。在两种NSCLC细胞系HCC193和H460中进行了MTS试验。通过膜联蛋白V试验以及针对裂解的半胱天冬酶-3、-8和IAPs的蛋白质印迹法对凋亡细胞死亡程度进行了表征。通过酶联免疫吸附测定法测定肿瘤坏死因子-α（TNF-α）的释放量。将放射敏感性与剂量增强比（DERs）进行了比较。HCC193细胞的D1143半数抑制浓度（IC50）为1μM。HCC193细胞在2.5μM D1143作用下，显示出明显的裂解半胱天冬酶-3、-8以及IAP水平降低；H460细胞在10μM D1143作用下也是如此，两者均呈时间依赖性。此外，HCC193细胞的TNF-α有所增加。D1143使细胞产生放射增敏作用：HCC193细胞，2.5μM D1143，孵育24小时，剂量增强比为2.19，p = 0.001；H460细胞，10μM D1143，孵育48小时，剂量增强比为1.29，p = 0.082。用放射疗法、TNF-α和D1143处理H460细胞可进一步使细胞产生放射增敏作用（剂量增强比为1.92，p = 0.026）。D1143在体外显著增强了HCC193和H460细胞的放射增敏作用。TNF-α在更敏感的细胞系（HCC193）中对增敏作用有贡献。有必要开展更多研究来检验D1143的作用机制，并评估其在临床环境中的体内潜力。
