Clusterin as a therapeutic target for radiation sensitization in a lung cancer model

Purpose: 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 and Materials: 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 How was compromised when mice bearing H460 xenografts were treated with OGX-011 and radiation. Conclusion: A combination of radiotherapy and OGX-011 improved control of tumor growth and vascular regression in the H460 lung cancer model. (c) 2005 Elsevier Inc.