Heat shock protein 27 as a new therapeutic target for radiation sensitization of head and neck squamous cell carcinoma.
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.
Université de Lyon, Université Lyon-I, Lyon, France.
Elie
E
Hadchity
Marie-Thérèse
MT
Aloy
Christian
C
Paulin
Emma
E
Armandy
Emmanuel
E
Watkin
Robert
R
Rousson
Martin
M
Gleave
Olivier
O
Chapet
Claire
C
Rodriguez-Lafrasse
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy; D045744:Cell Line, Tumor; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics* / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D055551:HSP27 Heat-Shock Proteins; D016376:Oligonucleotides, Antisense; D011838:Radiation-Sensitizing Agents