Radiosensitization of head and neck squamous cell carcinoma by a SMAC-mimetic compound, SM-164, requires activation of caspases.

Abstract

Chemoradiation is the treatment of choice for locally advanced head and neck squamous cell carcinoma (HNSCC). However, radioresistance, which contributes to local recurrence, remains a significant therapeutic problem. In this study, we characterized SM-164, a small second mitochondria-derived activator of caspase -mimetic compound that promotes degradation of cellular inhibitor of apoptosis-1(cIAP-1; also known as baculoviral IAP repeat-containing protein 2, BIRC2) and releases active caspases from the X-linked inhibitor of apoptosis inhibitory binding as a radiosensitizing agent in HNSCC cells. We found that SM-164 at nanomolar concentrations induced radiosensitization in some HNSCC cell lines in a manner dependent on intrinsic sensitivity to caspase activation and apoptosis induction. Blockage of caspase activation via short interfering RNA knockdown or a pan-caspase inhibitor, z-VAD-fmk, largely abrogated SM-164 radiosensitization. On the other hand, the resistant lines with a high level of Bcl-2 that blocks caspase activation and apoptosis induction became sensitive to radiation on Bcl-2 knockdown. Mechanistic studies revealed that SM-164 radiosensitization in sensitive cells was associated with NF-κB activation and TNFα secretion, followed by activation of caspase-8 and -9, leading to enhanced apoptosis. Finally, SM-164 also radiosensitized human tumor xenograft while causing minimal toxicity. Thus, SM-164 is a potent radiosensitizer via a mechanism involving caspase activation and holds promise for future clinical development as a novel class of radiosensitizer for the treatment of a subset of head and neck cancer patients.

• Authors: Jie Yang, Donna McEachern, Wenyan Li, Mary A Davis, Hua Li, Meredith A Morgan, Longchuan Bai, Jonathan T Sebolt, Haiying Sun, Theodore S Lawrence, Shaomeng Wang, Yi Sun
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 4 Pg. 658-69 (Apr 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21282353 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Bridged Bicyclo Compounds, Heterocyclic
• Caspase Inhibitors
• Cysteine Proteinase Inhibitors
• Inhibitor of Apoptosis Proteins
• Proto-Oncogene Proteins c-bcl-2
• Radiation-Sensitizing Agents
• SM 164
• Triazoles
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• BIRC3 protein, human
• Baculoviral IAP Repeat-Containing 3 Protein
• Ubiquitin-Protein Ligases
• Caspases

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Apoptosis (drug effects, radiation effects)
• Baculoviral IAP Repeat-Containing 3 Protein
• Blotting, Western
• Bridged Bicyclo Compounds, Heterocyclic (chemistry, pharmacology)
• Carcinoma, Squamous Cell (metabolism, pathology, therapy)
• Caspase Inhibitors
• Caspases (genetics, metabolism)
• Cell Line, Tumor
• Combined Modality Therapy
• Cysteine Proteinase Inhibitors (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects, radiation effects)
• Flow Cytometry
• Head and Neck Neoplasms (metabolism, pathology, therapy)
• Humans
• Inhibitor of Apoptosis Proteins (genetics, metabolism)
• Mice
• Mice, Nude
• Molecular Structure
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA Interference
• Radiation-Sensitizing Agents (chemistry, pharmacology)
• Radiotherapy (methods)
• Triazoles (chemistry, pharmacology)
• Ubiquitin-Protein Ligases
• Xenograft Model Antitumor Assays