Smac-mimetic compound SM-164 induces radiosensitization in breast cancer cells through activation of caspases and induction of apoptosis

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Radiotherapy is a treatment choice for local control of breast cancer, particularly after the removal of tumor tissues by surgery. However, intrinsic radioresistance of cancer cells limits therapeutic efficacy. Here, we determined in breast cancer cells the potential radiosensitizing activity of SM-164, a small molecule compound, that mimics the activity of SMAC, a mitochondrial protein released during apoptosis to activate caspases by inhibiting cellular inhibitor of apoptosis proteins, cIAP-1, and XIAP. We found that SM-164 at nanomolar concentrations promoted degradation of cIAP-1, disrupted the inhibitory binding of XIAP to active caspase-9, and sensitized breast cancer cells to radiation with a sensitization enhancement ratio (SER) of 1.7-1.8. In one line of breast cancer cells resistant to SM-164 as a single agent, SM-164 radiosensitization was mediated by intrinsic apoptosis pathway through activation of caspases-9 and -3. In a line of breast cancer cells sensitive to SM-164 as a single agent, SM-164 radiosensitization was mediated by both extrinsic and intrinsic apoptosis pathways through activation of caspases-9, -8, and -3. Consistently, blockage of caspase activation, through siRNA knockdown or treatment with a pan-caspase inhibitor z-VAD-fmk, inhibited apoptosis and abrogated SM-164 radiosensitization. Our study demonstrates that IAPs are valid radiosensitizing targets in breast cancer cells and SM-164 could be further developed as a novel class of radiosensitizers for the treatment of radioresistant breast cancer.