title: 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.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA. jiey123@hotmail.com
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.forename: Wenyan
authors.initials: W
authors.lastname: Li
authors.forename: Mary A
authors.initials: MA
authors.lastname: Davis
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Morgan
authors.forename: Longchuan
authors.initials: L
authors.lastname: Bai
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Sebolt
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology; D011878:Radiotherapy / Q000379:methods; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases; D023041:Xenograft Model Antitumor Assays
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D019086:Bridged Bicyclo Compounds, Heterocyclic; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011838:Radiation-Sensitizing Agents; C533467:SM 164; D014230:Triazoles; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D020169:Caspases