Radiosensitization of head and neck squamous cell carcinoma by a SMAC-mimetic compound, SM-164, requires activation of caspases.
Radiosensitization of head and neck squamous cell carcinoma by a SMAC-mimetic compound, SM-164, requires activation of caspases.
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DOI：
10.1158/1535-7163.mct-10-0643
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发表时间：
2011-04
影响因子：
5.7
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Yang J;McEachern D;Li W;Davis MA;Li H;Morgan MA;Bai L;Sebolt JT;Sun H;Lawrence TS;Wang S;Sun Y
放化疗是局部晚期头颈鳞状细胞癌 (HNSCC) 的首选治疗方法。然而，导致局部复发的放射抗性仍然是一个重要的治疗问题。在这项研究中，我们对 SM-164 进行了表征，SM-164 是一种小型 SMAC 模拟化合物，可促进 cIAP-1（也称为 BIRC2）降解并从 XIAP 抑制性结合中释放活性半胱天冬酶，作为 HNSCC 细胞中的放射增敏剂。我们发现纳摩尔浓度的 SM-164 在一些 HNSCC 细胞系中诱导放射增敏，其方式依赖于对 caspase 激活和细胞凋亡诱导的内在敏感性。通过 siRNA 敲低或泛 caspase 抑制剂 z-VAD-fmk 阻断 caspase 激活，很大程度上消除了 SM-164 放射增敏作用。另一方面，具有高水平 BCL-2（阻止 caspase 激活和细胞凋亡诱导）的抗性株系在 BCL-2 敲低后变得对辐射敏感。机制研究表明，SM-164 在敏感细胞中的放射增敏作用与 NFκB 激活和 TNFα 分泌有关，随后激活 caspase-8 和 -9，导致细胞凋亡增强。最后，SM-164 还可以对人类肿瘤异种移植物进行放射增敏，同时引起最小的毒性。因此，SM-164 通过涉及 caspase 激活的机制成为一种有效的放射增敏剂，并有望作为一类新型放射增敏剂用于治疗部分头颈癌患者的未来临床开发。
Chemoradiation is the treatment of choice for locally advanced head and neck squamous cell carcinoma (HNSCC). However, radioresistance, which contributes to local recurrence, remains a significant therapeutic problem. In this study, we characterized SM-164, a small SMAC mimetic compound that promotes degradation of cIAP-1 (also known as BIRC2) and releases active caspases from XIAP inhibitory binding, as a radiosensitizing agent in HNSCC cells. We found that SM-164 at nanomolar concentrations induced radiosensitization in some HNSCC cell lines in a manner dependent on intrinsic sensitivity to caspase activation and apoptosis induction. Blockage of caspase activation via siRNA knockdown or a pan-caspase inhibitor, z-VAD-fmk largely abrogated SM-164 radiosensitization. On the other hand, the resistant lines with a high level of BCL-2 that blocks caspase activation and apoptosis induction became sensitive to radiation upon BCL-2 knockdown. Mechanistic studies revealed that SM-164 radiosensitization in sensitive cells was associated with NFκB activation and TNFα secretion, followed by activation of caspases-8 and -9, leading to enhanced apoptosis. Finally, SM-164 also radiosensitized human tumor xenograft, while causing minimal toxicity. Thus, SM-164 is a potent radiosensitizer via a mechanism involving caspase activation and holds promise for future clinical development as a novel class of radiosensitizer for the treatment of a subset of head and neck cancer patients.