The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma. Issue 3 (September 2015)

• Record Type: Journal Article
• Authors: Matzinger, Oscar; Viertl, David; Tsoutsou, Pelagia; Kadi, Linda; Rigotti, Stefania; Zanna, Claudio; Wiedemann, Norbert; Vozenin, Marie-Catherine; Vuagniaux, Grégoire; Bourhis, Jean
• Is Part Of: Radiotherapy and oncology. Volume 116:Issue 3(2015:Sep.)
• Page Start: 495
• Page End: 503
• Publication Date: 2015-09
• Subjects: Oncology -- Periodicals; Radiotherapy -- Periodicals; Tumors -- Periodicals; Medical Oncology -- Periodicals; Neoplasms -- radiotherapy -- Periodicals; Radiotherapy -- Periodicals; Radiothérapie -- Périodiques; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9940642
• DOI: 10.1016/j.radonc.2015.05.017
• Languages: English
• ISSNs: 0167-8140

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title id="st005">Abstract</title> <sec> <title id="st334">Background and purpose</title> <p id="sp0005">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.</p> </sec> <sec> <title id="st011">Material and methods</title> <p id="sp0011">The present study was designed to investigate the radiosensitizing effect and optimal sequence of administration of the novel SMAC-mimetic Debio 1143 <italic>in vitro</italic> and <italic>in vivo</italic>. Apoptosis, alteration of DNA damage repair (DDR), and tumor necrosis factor-alpha (TNF-α) signaling were examined.</p> </sec> <sec> <title id="st012">Results</title> <p id="sp0012"> <italic>In vitro</italic>, 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. <italic>In vivo</italic>, 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.</p> </sec> <sec> <title id="st013">Conclusions</title> <p id="sp0013">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.</p> </sec> </abstract>