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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Apoptosis / drug effects
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Apoptosis / radiation effects
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Baculoviral IAP Repeat-Containing 3 Protein
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Blotting, Western
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Carcinoma, Squamous Cell / therapy*
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Caspase Inhibitors
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Caspases / genetics
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Caspases / metabolism*
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Cell Line, Tumor
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Combined Modality Therapy
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Cysteine Proteinase Inhibitors / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Enzyme Activation / radiation effects
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Flow Cytometry
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Head and Neck Neoplasms / metabolism
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Head and Neck Neoplasms / pathology
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Head and Neck Neoplasms / therapy*
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Humans
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Mice
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Mice, Nude
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Molecular Structure
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA Interference
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Radiation-Sensitizing Agents / chemistry
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Radiation-Sensitizing Agents / pharmacology
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Radiotherapy / methods
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Triazoles / chemistry
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Triazoles / pharmacology*
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Ubiquitin-Protein Ligases
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Xenograft Model Antitumor Assays
Substances
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Amino Acid Chloromethyl Ketones
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Bridged Bicyclo Compounds, Heterocyclic
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Inhibitor of Apoptosis Proteins
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Proto-Oncogene Proteins c-bcl-2
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Radiation-Sensitizing Agents
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SM 164
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Triazoles
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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BIRC3 protein, human
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Baculoviral IAP Repeat-Containing 3 Protein
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Ubiquitin-Protein Ligases
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Caspases