Oral Squamous Cell Carcinoma (OSCC) is the 6th most common cancer worldwide. It is generally aggressive and closely associated with chemoresistance and poor survival. There is accumulating evidence for the involvement of inhibitors of apoptosis proteins (IAPs), including IAP1 and XIAP, in mediating chemotherapy resistance in OSCC. Various strategies for targeting IAPs have been designed and tested in recent years and several small molecule IAP inhibitors are in clinical trials as monotherapies as well as in combination with radiotherapy and chemotherapy. The purpose of this study was to evaluate and compare the efficacy and biological activity of three IAP inhibitors both as stand-alone and sensitising agents to cisplatin in a preclinical model of squamous cell carcinoma of the tongue. Cisplatin-sensitive SCC4 and -resistant SCC4cisR cells were utilised in this study. Apoptosis was evaluated by flow cytometric analysis of Annexin V/Propidium Iodide-stained cells. Expression of IAP proteins was determined by western blotting and knockdown of cIAP1, livin and XIAP was conducted by transfection of cells with siRNA. We establish for the first time the therapeutic efficacy of the Smac mimetic, BV6 and the XIAP inhibitor Embelin, for OSCC. Both of these IAP targeting agents synergistically enhanced cisplatin-mediated apoptotic cell death in resistant cells which was mediated in part by depletion of XIAP. In addition, knockdown of XIAP using siRNA enhanced cisplatin-mediated cell death, demonstrating the importance of targeting XIAP in this sensitisation. These findings provide pre-clinical evidence that IAP inhibition may be a valuable therapeutic option in OSCC.

中文翻译：

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靶向凋亡蛋白抑制剂（IAP）增强口腔鳞癌细胞对顺铂的敏感性

口腔鳞状细胞癌（OSCC）是全球第六大常见癌症。它通常具有侵袭性，并且与化疗耐药和生存率低密切相关。越来越多的证据表明凋亡蛋白抑制剂 (IAP)（包括 IAP1 和 XIAP）参与介导 OSCC 的化疗耐药。近年来，已经设计和测试了各种针对 IAP 的策略，并且几种小分子 IAP 抑制剂正在作为单一疗法以及与放疗和化疗相结合的临床试验中。本研究的目的是评估和比较三种 IAP 抑制剂在舌鳞状细胞癌临床前模型中作为顺铂独立药物和敏化剂的疗效和生物活性。本研究使用顺铂敏感的 SCC4 和耐药的 SCC4cisR 细胞。通过膜联蛋白 V/碘化丙啶染色细胞的流式细胞术分析评估细胞凋亡。通过蛋白质印迹法测定IAP蛋白的表达，并通过用siRNA转染细胞来敲除cIAP1、livin和XIAP。我们首次确定了 Smac 模拟物 BV6 和 XIAP 抑制剂 Embelin 对 OSCC 的治疗功效。这两种 IAP 靶向剂协同增强耐药细胞中顺铂介导的细胞凋亡，该死亡部分是由 XIAP 耗竭介导的。此外，使用 siRNA 敲低 XIAP 增强了顺铂介导的细胞死亡，证明了靶向 XIAP 在这种敏化中的重要性。这些发现提供了临床前证据，表明 IAP 抑制可能是 OSCC 的一种有价值的治疗选择。