AT-101, a Pan-Bcl-2 Inhibitor, Leads to Radiosensitization of Non-small Cell Lung Cancer
AT-101, a Pan-Bcl-2 Inhibitor, Leads to Radiosensitization of Non-small Cell Lung Cancer
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DOI：
10.1097/jto.0b013e3181d6e08e
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发表时间：
2010-05-01
影响因子：
20.4
通讯作者：
Lu, Bo
中科院分区：
文献类型：
--
作者：
Moretti, Luigi;Li, Bo;Lu, Bo
介绍：放射治疗在肺癌的治疗中起着核心作用。然而，其有效性通常是有限的，部分原因是关键凋亡调节因子（如Bcl-2家族成员）的缺陷，这些缺陷有助于癌症逃避凋亡的能力。在这项研究中，我们测试AT-101，泛Bcl-2抑制剂，作为一个潜在的放射增敏剂在肺癌。方法和结果：克隆形成试验被用来确定多个肺癌细胞系的放射敏感性。根据肺癌细胞对放疗的相对反应，将其分为两组，并选择每组的代表性细胞系进行更深入的研究：A549（耐药）和HCC 2429（敏感）。测定各组的抗凋亡（Bcl-2、Bcl-X-L和Mcl-1）和促凋亡（Bax、巴克和Bid）Bcl-2蛋白的表达水平。虽然Bcl-2和Mcl-1的水平在两组中均较低，但Bcl-X-L在A549中的表达显著较高，而在HCC 2429中几乎未检测到。与A549相比，HCC 2429中Bax/巴克的水平高40%。当单独给药时，AT-101以浓度依赖性方式导致两组细胞凋亡增加，即使在较低浓度下，在HCC 2429中的活性也增强。AT-101对A549和HCC 2429细胞的放射敏感性有明显的增强作用（p < 0.005）。与3-（4，5-Dimethylthiazol-2-yl）-2，5-diphenyltetrazolium bromide检测结果一致，A549细胞需要增加AT-101剂量以达到与HCC 2429细胞相似的细胞毒性。进一步的临床研究是必要的，以评估AT-101作为提高肺癌放射治疗率的药物的潜力。
Introduction: Radiotherapy has a central role in the treatment of lung cancer. However, its effectiveness is often limited, in part, because of the defects in key apoptosis regulators, such as Bcl-2 family members, that contribute to cancer ability to evade apoptosis. In this study, we tested AT-101, a pan-Bcl-2 inhibitor, as a potential radiosensitizer in lung cancer.Methods and Results: Clonogenic assays were used to determine the radiosensitivity of multiple lung cancer cell lines. On the basis of their relative response to radiotherapy, lung cancer cells were stratified into two groups, and a representative cell line of each group was selected for more in-depth study: A549 (resistant) and HCC2429 (sensitive). The expression levels of antiapoptotic (Bcl-2, Bcl-X-L, and Mcl-1) and proapoptotic (Bax, Bak, and Bid) Bcl-2 proteins were determined for each group. Although the levels of Bcl-2 and Mcl-1 were low for both groups, Bcl-X-L expression was dramatically higher in A549, whereas almost not detected in HCC2429. The levels of Bax/Bak were 40% higher in HCC2429 compared with A549. When administered alone, AT-101 resulted in increased apoptosis in concentration-dependent manner against both groups, with enhanced activity in HCC2429 even at lower concentration. Furthermore, AT-101 promoted radiosensitivity of A549 and HCC2429 cells (p < 0.005). Consistent with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay findings, A549 cells required increased AT-101 dose to achieve a similar cytoxicity to HCC2429 cells.Conclusions: These investigations suggest that the Bcl-2 family may serve as effective therapeutic targets in lung cancer. Further clinical studies are warranted to assess the potential of AT-101 as an agent that enhances the therapeutic ratio of radiotherapy in lung cancer.