Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
    Datensatz exportieren als...
  • BibTeX
LCL161, a SMAC-mimetic, Preferentially Radiosensitizes Human Papillomavirus-negative Head and Neck Squamous Cell Carcinoma
Molecular cancer therapeutics, 2019-06, Vol.18 (6), p.1025-1035
2019

Details

Autor(en) / Beteiligte
Titel
LCL161, a SMAC-mimetic, Preferentially Radiosensitizes Human Papillomavirus-negative Head and Neck Squamous Cell Carcinoma
Ist Teil von
  • Molecular cancer therapeutics, 2019-06, Vol.18 (6), p.1025-1035
Ort / Verlag
United States
Erscheinungsjahr
2019
Link zum Volltext
Quelle
EZB Free E-Journals
Beschreibungen/Notizen
  • Targeting inhibitor of apoptosis proteins (IAP) with second mitochondria-derived activator of caspase (SMAC) mimetics may promote cancer cell death. We tested whether cIAP1 predicts poor prognosis in head and neck squamous cell carcinoma (HNSCC) and whether a novel Smac-mimetic, LCL161, could radiosensitize human papillomavirus-positive (HPV ) and -negative (HPV ) HNSCC. The association of (encoding cIAP1) mRNA level with HPV status in HNSCC was analyzed using The Cancer Genome Atlas (TCGA) database. cIAP1 was assessed by IHC on an HNSCC tissue microarray (TMA, = 84) followed by correlation analysis with HPV status and patient outcomes. Human cell culture and animal models of HNSCC were used to analyze the outcome and molecular characteristics following radiotherapy in combination with LCL161. cIAP1 expression is increased in HPV compared with HPV HNSCC tumors in the TCGA database. In our TMA, cIAP1 was overexpressed in HNSCC compared with normal tissues ( = 0.0003) and associated with a poor overall survival ( = 0.0402). cIAP1 levels were higher in HPV than that in HPV HNSCC tumors ( = 0.004) and patients with cIAP1 /HPV HNSCC had the worst survival. LCL161 effectively radiosensitized HPV HNSCC cells, which was accompanied with enhanced apoptosis, but not HPV HNSCC cells. Importantly, LCL161 in combination with radiotherapy led to dramatic tumor regression of HPV HNSCC tumor xenografts, accompanied by cIAP1 degradation and apoptosis activation. These results reveal that cIAP1 is a prognostic and a potential therapeutic biomarker for HNSCC, and targeting cIAP1 with LCL161 preferentially radiosensitizes HPV HNSCC, providing justification for clinical testing of LCL161 in combination with radiation for patients with HPV HNSCC.
Sprache
Englisch
Identifikatoren
ISSN: 1535-7163
eISSN: 1538-8514
DOI: 10.1158/1535-7163.MCT-18-1157
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6548673
Format
–
Schlagworte
Aged, Animals, Apoptosis - drug effects, Apoptosis - radiation effects, Apoptosis Regulatory Proteins - chemistry, Biomarkers, Tumor - genetics, Biomarkers, Tumor - metabolism, Cell Line, Tumor, Female, Head and Neck Neoplasms - drug therapy, Head and Neck Neoplasms - pathology, Head and Neck Neoplasms - radiotherapy, Head and Neck Neoplasms - virology, Humans, Inhibitor of Apoptosis Proteins - genetics, Inhibitor of Apoptosis Proteins - metabolism, Male, Mice, Mice, Nude, Middle Aged, Mitochondrial Proteins - chemistry, Molecular Mimicry, Papillomaviridae - isolation & purification, Papillomavirus Infections - virology, Prognosis, Radiation-Sensitizing Agents - pharmacology, Radiation-Sensitizing Agents - therapeutic use, Squamous Cell Carcinoma of Head and Neck - drug therapy, Squamous Cell Carcinoma of Head and Neck - pathology, Squamous Cell Carcinoma of Head and Neck - radiotherapy, Squamous Cell Carcinoma of Head and Neck - virology, Thiazoles - pharmacology, Thiazoles - therapeutic use, Tumor Burden - drug effects, Tumor Burden - radiation effects, Ubiquitin-Protein Ligases - genetics, Ubiquitin-Protein Ligases - metabolism, Xenograft Model Antitumor Assays

Weiterführende Literatur

Empfehlungen zum selben Thema automatisch vorgeschlagen von bX