The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma.
Détails
ID Serval
serval:BIB_BFF3A5A037D6
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma.
Périodique
Radiotherapy and Oncology : Journal of the European Society For Therapeutic Radiology and Oncology
ISSN
1879-0887 (Electronic)
ISSN-L
0167-8140
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
116
Numéro
3
Pages
495-503
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
BACKGROUND AND PURPOSE: 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.
MATERIAL AND 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.
MATERIAL AND 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.
Mots-clé
Animals, Antineoplastic Agents/pharmacology, Apoptosis/drug effects, Azocines/pharmacology, Benzhydryl Compounds/pharmacology, Carcinoma, Squamous Cell/therapy, Caspase 3/metabolism, Cell Death/drug effects, Cell Line, Tumor, Chemoradiotherapy/methods, Female, Head and Neck Neoplasms/therapy, Humans, Inhibitor of Apoptosis Proteins/antagonists & inhibitors, Intracellular Signaling Peptides and Proteins/pharmacology, Mice, Inbred Strains, Mitochondrial Proteins/pharmacology, Neoplasm Transplantation, Radiation-Sensitizing Agents/pharmacology, Signal Transduction/drug effects, Transplantation, Heterologous, Tumor Necrosis Factor-alpha/physiology, Xenograft Model Antitumor Assays/methods
Pubmed
Web of science
Création de la notice
03/07/2015 11:27
Dernière modification de la notice
20/08/2019 16:34