Clusterin as a therapeutic target for radiation sensitization in a lung cancer model.
OBJECTIVE
Clusterin plays important roles in cell survival and death. Inactivation of clusterin enhances the therapeutic efficacy of chemotherapy in lung cancer models. The purpose of this study was to determine whether inhibition of clusterin by an antisense-based investigative drug enhances radiation sensitization in a lung cancer model.


METHODS
Cells were transfected with an antisense oligonucleotide (ASO) against clusterin (OGX-011). Apoptosis was determined by 7-aminoactinomycin D staining. Cell survival was examined by 3-(4, 5-methylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) and clonogenic assay. Xenograft model was used to demonstrate tumor growth and tumor blood flow.


RESULTS
OGX-011 specifically attenuated the expression of secreted clusterin (prosurvival), with no apparent effect on the expression of nuclear clusterin (proapoptotic). Apoptosis was significantly increased when H460 lung cancer cells were treated with OGX-011 plus radiation. Inhibition of clusterin followed by radiation greatly decreased cell survival. H460 xenografts that were treated with OGX-011 plus radiotherapy demonstrated growth delay beyond 17 days. Doppler studies showed that tumor blood flow was compromised when mice bearing H460 xenografts were treated with OGX-011 and radiation.


CONCLUSIONS
A combination of radiotherapy and OGX-011 improved control of tumor growth and vascular regression in the H460 lung cancer model.
Cao
Carolyn
C
Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-5671, USA.
Shinohara
Eric T
ET
Li
Hecheng
H
Niermann
Ken J
KJ
Kim
Kwang Woon
KW
Sekhar
Konjeti R
KR
Gleave
Martin
M
Freeman
Michael
M
Lu
Bo
B
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D051152:Clusterin / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D013873:Thionucleotides / Q000627:therapeutic use*; D014162:Transfection; D014183:Transplantation, Heterologous
D051152:Clusterin; D009363:Neoplasm Proteins; C503781:OGX-011; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides