Breast Cancer Research and Treatment

, Volume 133, Issue 1, pp 189–199 | Cite as

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

  • Dong Yang
  • Yongchao Zhao
  • Amy Y. Li
  • Shaomeng Wang
  • Gongxian WangEmail author
  • Yi SunEmail author
Preclinical study


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.


Apoptosis Caspase activation XIAP cIAP-1 degradation Radiosensitization 



We would like to thank Dr. John Silke at La Trobe University, Australia for anti-cIAP-1 antibody and Dr. Colin Duckett at University of Michigan for HA-XIAP plasmid. This work is supported by the National Cancer Institute (NCI) grants (CA111554, CA118762, and CA156744) to Yi Sun and the Nanchang University Scholarship Fund in China to Dong Yang. Dr. Shaomeng Wang is associated with Ascenta as a consultant and stock holder. He also receives funding from Ascenta


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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  1. 1.Division of Radiation and Cancer Biology, Department of Radiation OncologyUniversity of MichiganAnn ArborUSA
  2. 2.Department of Orthopaedicsthe First Affiliated Hospital of Nanchang UniversityNanchangChina
  3. 3.Department of Internal MedicineUniversity of MichiganAnn ArborUSA
  4. 4.Department of Urologythe First Affiliated Hospital of Nanchang UniversityNanchangChina

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