Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528 Frankfurt, Germany.
Cancer Treat Rev. 2012 Oct;38(6):760-6. doi: 10.1016/j.ctrv.2012.01.005. Epub 2012 Feb 18.
Radiotherapy initiates a variety of signaling events in cancer cells that eventually lead to cell death in case the DNA damage cannot be repaired. However, the signal transduction pathways that mediate cell death in response to radiation-inflicted DNA damage are frequently disturbed in human cancers, contributing to radioresistance. For example, aberrant activation of antiapoptotic programs such as high expression of Inhibitor of Apoptosis (IAP) proteins has been shown to interfere with the efficacy of radiotherapy. Since IAP proteins have been linked to radioresistance in several malignancies, therapeutic targeting of IAP proteins may open new perspectives to overcome radioresistance. Therefore, molecular targeting of IAP proteins may provide novel opportunities to reactivate cell death pathways that mediate radiation-induced cytotoxicity. A number of strategies have been developed in recent years to antagonize IAP proteins for the treatment of cancers. Some of these approaches have already been translated into a clinical application. While IAP protein-targeting agents are currently being evaluated in early clinical trials alone or in combination with conventional chemotherapy, they have not yet been tested in combination with radiation therapy. Therefore, it is a timely subject to discuss the opportunities of antagonizing IAP proteins for radiosensitization. Preclinical studies demonstrating the potential of this concept in relevant in vitro and in vivo models underscore that this combination approach warrants further clinical investigation. Thus, combination protocols using IAP antagonists together with radiotherapy may pave the avenue to more effective radiation-based treatment options for cancer patients.
放射治疗会在癌细胞中引发多种信号事件，如果不能修复 DNA 损伤，最终会导致细胞死亡。然而，在人类癌症中，介导细胞死亡的信号转导途径经常受到干扰，导致放射抵抗。例如，已经表明，凋亡抑制程序（如凋亡抑制蛋白（IAP）蛋白的高表达）的异常激活会干扰放射治疗的疗效。由于 IAP 蛋白与多种恶性肿瘤的放射抵抗有关，因此靶向 IAP 蛋白的治疗可能为克服放射抵抗开辟新的前景。因此，针对 IAP 蛋白的分子靶向可能为重新激活介导辐射诱导细胞毒性的细胞死亡途径提供新的机会。近年来已经开发了许多针对 IAP 蛋白的策略来治疗癌症。其中一些方法已经转化为临床应用。虽然 IAP 蛋白靶向药物目前正在单独或与常规化疗联合进行早期临床试验评估，但尚未与放射治疗联合进行测试。因此，讨论拮抗 IAP 蛋白以增强放射敏感性的机会是及时的。在相关的体外和体内模型中进行的临床前研究证明了这一概念的潜力，强调了这种联合方法值得进一步临床研究。因此，使用 IAP 拮抗剂联合放射治疗的联合方案可能为癌症患者提供更有效的基于放射的治疗选择。
