XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer.
Survivin and XIAP are members of inhibitors of apoptosis (IAPs) family. They are upregulated in various malignancies. Inactivation of these molecules has resulted in chemosensitization. The purpose of this study was to determine whether inhibition of survivin, XIAP, or both enhances radiotherapy in a lung cancer model. Transient transfection of H460 cells with antisense oligonucleotides (ASOs) against either molecule has specifically reduced their expression, by Western analysis. Results from 3-(4,5-methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and clonogenic assays suggest that inhibition of survivin or XIAP greatly decreased cell survival following irradiation. A significantly increased number of apoptotic cells were detected when H460 cells were treated with either antisurvivin, anti-XIAP or both ASOs (P=0.03, 0.0003 and 0.01, respectively) plus irradiation. H460 xenografts that were treated with ASOs plus radiotherapy demonstrated growth delay beyond 15 days. Growth delay in the groups of combined treatment was greater than that in other groups. However, treatment with ASOs alone did not affect tumor growth delay in mice, but decreased the survival of H460 cells in culture. Antisense treatment did not cause any mortality or weight loss during the 32 days of study. These data suggest that inhibition of survivin or XIAP radiosensitizes H460 lung cancer cells by upregulating apoptosis and downregulating cell survival. Combination of radiotherapy and inhibition of survivin and XIAP through the antisense approach results in improved tumor control by radiotherapy in a mouse model of lung cancer.
Cao
Carolyn
C
Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, 1301 22nd Avenue South, B-902 The Vanderbilt Clinic, Nashville, TN 37232-5671, USA.
Mu
Yi
Y
Hallahan
Dennis E
DE
Lu
Bo
B
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000532:radiotherapy*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors*; D011838:Radiation-Sensitizing Agents / Q000528:radiation effects*; D000077022:Survivin; D014183:Transplantation, Heterologous; D051636:X-Linked Inhibitor of Apoptosis Protein; D016335:Zinc Fingers
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins; D011838:Radiation-Sensitizing Agents; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein