title: The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma.
abstract: OBJECTIVE
  Second mitochondria-derived activator of caspase (SMAC)-mimetics are a new class of targeted drugs that specifically induce apoptotic cancer cell death and block pro-survival signaling by antagonizing selected members of the inhibitor of apoptosis protein (IAP) family.
  
  
  METHODS
  The present study was designed to investigate the radiosensitizing effect and optimal sequence of administration of the novel SMAC-mimetic Debio 1143 in vitro and in vivo. Apoptosis, alteration of DNA damage repair (DDR), and tumor necrosis factor-alpha (TNF-α) signaling were examined.
  
  
  RESULTS
  In vitro, Debio 1143 displayed anti-proliferative activity and enhanced intrinsic radiation sensitivity in 5/6 head and neck squamous cell carcinoma (HNSCC) cell lines in a synergistic manner. In vivo, Debio 1143 dose-dependently radio-sensitized FaDu and SQ20B xenografts, resulting in complete tumor regression in 8/10 FaDu-xenografted mice at the high dose level. At the molecular level, Debio 1143 combined with radiotherapy (RT) induced enhancement of caspase-3 activity, increase in Annexin V-positive cells and karyopyknosis, and increase in TNF-α mRNA levels. Finally, in a neutralization experiment using a TNF-α-blocking antibody and a caspase inhibitor, it was shown that the radiosensitizing effect of Debio 1143 is mediated by caspases and TNF-α.
  
  
  CONCLUSIONS
  These results demonstrate that the novel SMAC-mimetic Debio 1143 is a radiosensitizing agent that is worthy of further investigation in clinical trials in combination with radiotherapy.
authors.affiliation: Laboratory of Radiation Oncology Department, University Hospital of Lausanne (CHUV), Switzerland; Radiation Oncology Department, Hôpital Riviera-Chablais, Vevey, Switzerland.
authors.forename: Oscar
authors.initials: O
authors.lastname: Matzinger
authors.affiliation: Laboratory of Radiation Oncology Department, University Hospital of Lausanne (CHUV), Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Viertl
authors.affiliation: Laboratory of Radiation Oncology Department, University Hospital of Lausanne (CHUV), Switzerland; Radiation Oncology Department Hôpital du Valais, Sion, Switzerland.
authors.forename: Pelagia
authors.initials: P
authors.lastname: Tsoutsou
authors.affiliation: Debiopharm International SA, Lausanne, Switzerland.
authors.forename: Linda
authors.initials: L
authors.lastname: Kadi
authors.affiliation: Debiopharm International SA, Lausanne, Switzerland.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rigotti
authors.affiliation: Debiopharm International SA, Lausanne, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Zanna
authors.affiliation: Debiopharm International SA, Lausanne, Switzerland.
authors.forename: Norbert
authors.initials: N
authors.lastname: Wiedemann
authors.affiliation: Laboratory of Radiation Oncology Department, University Hospital of Lausanne (CHUV), Switzerland. Electronic address: marie-catherine.vozenin@chuv.ch.
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Vozenin
authors.affiliation: Debiopharm International SA, Lausanne, Switzerland.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vuagniaux
authors.affiliation: Laboratory of Radiation Oncology Department, University Hospital of Lausanne (CHUV), Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001392:Azocines / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods; D005260:Female; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D008815:Mice, Inbred Strains; D024101:Mitochondrial Proteins / Q000494:pharmacology; D009368:Neoplasm Transplantation; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001392:Azocines; D001559:Benzhydryl Compounds; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; D011838:Radiation-Sensitizing Agents; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3
keywords: HNSCC; IAP inhibitor; Radiosensitizer; SMAC-mimetic