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.
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