Heat shock protein 27 as a new therapeutic target for radiation sensitization of head and neck squamous cell carcinoma

Autor: Martin E. Gleave, O. Chapet, Emmanuel Watkin, Elie Hadchity, Christian Paulin, Emma Armandy, Claire Rodriguez-Lafrasse, Robert Rousson, Marie-Thérèse Aloy
Přispěvatelé: Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de Cardiogénétique, Hospices Civils de Lyon (HCL), LIGUE CANCER AIN - SAVOIE - SAONE ET LOIRE ETOILE Contrat plan Etat région
Jazyk: angličtina
Rok vydání: 2009
Předmět:
MESH: Radiation-Sensitizing Agents
Radiation-Sensitizing Agents
medicine.medical_treatment
HSP27 Heat-Shock Proteins
Apoptosis
Mice
0302 clinical medicine
MESH: Oligonucleotides
Antisense
Drug Discovery
MESH: Animals
0303 health sciences
MESH: Carcinoma
Squamous Cell
Immunohistochemistry
3. Good health
Head and Neck Neoplasms
030220 oncology & carcinogenesis
Carcinoma
Squamous Cell
Molecular Medicine
Female
MESH: Xenograft Model Antitumor Assays
MESH: Cell Line
Tumor
Mice
Nude
Biology
03 medical and health sciences
Hsp27
In vivo
Radioresistance
Cell Line
Tumor
Genetics
medicine
MESH: Mice
Nude
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
MESH: HSP27 Heat-Shock Proteins
Clonogenic assay
Molecular Biology
Protein kinase B
MESH: Mice
PI3K/AKT/mTOR pathway
030304 developmental biology
Pharmacology
MESH: Humans
MESH: Apoptosis
MESH: Immunohistochemistry
Original Articles
Oligonucleotides
Antisense
medicine.disease
Head and neck squamous-cell carcinoma
Xenograft Model Antitumor Assays
Radiation therapy
MESH: Head and Neck Neoplasms
Immunology
biology.protein
Cancer research
MESH: Female
Zdroj: Molecular Therapy
Molecular Therapy, Cell Press, 2009, 17 (8), pp.1387-94. ⟨10.1038/mt.2009.90⟩
ISSN: 1525-0016
1525-0024
Popis: International audience; In a wide range of human cancers, increased levels of heat shock protein 27 (Hsp27) are closely associated with tumorigenesis, metastasis, resistance to anticancer therapeutics, and thus poor prognosis. In this study, we evaluate the radiosensitizing effects of Hsp27 gene silencing using OGX-427, a second-generation antisense oligonucleotide (ASO), on the radioresistant head and neck squamous cell carcinoma (HNSCC) SQ20B cells. In vitro, the downregulation of Hsp27 significantly enhanced radiation-induced apoptotic and clonogenic death, and promoted Akt inactivation. In vivo, combining OGX-427 with local tumor irradiation (5 x 2 Gy) led to a significant regression of SQ20B tumors related to a high rate of apoptosis and decreased levels of glutathione antioxidant defenses. Increasing the total radiation dose (15 x 2 Gy) significantly amplified the radiosensitizing effect of OGX-427. Treatment of tumors with OGX-427 plus radiation resulted in a decrease in angiogenesis associated with a reduced activation of the Akt pathway. Furthermore, the combined treatment enhanced the survival of SQ20B-bearing mice and showed no signs of acute and delayed toxicity. Our findings demonstrate for the first time that Hsp27 knockdown enhances the cytotoxic effects of radiotherapy in vivo and provide preclinical proof of principle for clinical trials using Hsp27 antisense technology in the treatment of patients with HNSCC radioresistant cancers.
Databáze: OpenAIRE
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