Corresponding Authors: Yi-Xin Zeng, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China.
Mol Cancer Ther. 2013 Sep;12(9):1728-37. doi: 10.1158/1535-7163.MCT-13-0017. Epub 2013 May 22.
Nasopharyngeal carcinoma is a common malignancy in Southern China. After radiotherapy and chemotherapy, a considerable proportion of patients with nasopharyngeal carcinoma suffered tumor relapse and metastasis. Cancer stem cells (CSC) have been shown with resistance against therapies and thus considered as the initiator of recurrence and metastasis in tumors, where the antiapoptotic property of CSCs play an important role. Smac/DIABLO is an inverse regulator for the inhibitors of apoptosis protein family (IAP), which have been involved in apoptosis. Here, the effects of Smac mimetics on the CSCs of nasopharyngeal carcinoma were studied both in vitro and in vivo, using two clones of nasopharyngeal carcinoma cell line CNE2 as models. We found that one of the clones, S18, had CSC-like properties and IAPs were overexpressed. The combination of Smac mimetics and TNF-related apoptosis-inducing ligand (TRAIL) can reduce the percentage of SP cells and inhibit the colony- and sphere-forming abilities of S18 cells, indicating their ability to attenuate the CSCs. Moreover, in a nasopharyngeal carcinoma xenograft model, the administration of Smac mimetics in combination with TRAIL also led to the elimination of nasopharyngeal carcinoma stem cells. Furthermore, the Smac mimetics in combination with TRAIL induced the degradation of cIAP1 and XIAP and thus induced apoptosis in vitro and in vivo. Taken together, our data show that Smac mimetics exerted an antitumor effect on nasopharyngeal carcinoma cancer stem cells, and this combination treatment should be considered as a promising strategy for the treatment of nasopharyngeal carcinoma.
鼻咽癌是中国南方地区常见的恶性肿瘤。经过放化疗后，相当一部分鼻咽癌患者出现肿瘤复发和转移。癌症干细胞（CSC）具有耐药性，被认为是肿瘤复发和转移的启动子，其中 CSC 的抗凋亡特性起着重要作用。Smac/DIABLO 是凋亡抑制剂蛋白家族（IAP）的反向调节剂，参与凋亡。在这里，我们使用两种鼻咽癌细胞系 CNE2 的克隆作为模型，研究了 Smac 模拟物对鼻咽癌 CSC 的体内外作用。我们发现，其中一个克隆 S18 具有 CSC 样特性，并且 IAPs 过表达。Smac 模拟物与 TNF 相关凋亡诱导配体（TRAIL）的联合使用可以降低 SP 细胞的比例，并抑制 S18 细胞的集落和球体形成能力，表明它们能够减弱 CSC。此外，在鼻咽癌异种移植模型中，Smac 模拟物联合 TRAIL 的给药也导致了鼻咽癌干细胞的消除。此外，Smac 模拟物联合 TRAIL 诱导 cIAP1 和 XIAP 的降解，从而在体外和体内诱导细胞凋亡。总之，我们的数据表明，Smac 模拟物对鼻咽癌癌症干细胞具有抗肿瘤作用，这种联合治疗应被视为治疗鼻咽癌的有前途的策略。
