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Antisense Oligonucleotides Targeting XIAP Induce Apoptosis and Enhance Chemotherapeutic Activity against Human Lung Cancer Cells in Vitro and in Vivo¹

Department of Advanced Therapeutics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada [Y. H., V. D., L. D. M.]; Celator Technologies Inc., Vancouver, British Columbia, Canada [L. D. M.]; Departments of Pediatrics, and of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, K1H 8M5 Canada [S. B., R. G. K.]; Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada [S. B., R. G. K.]; and Aegera Oncology Inc., Ottawa, Ontario, Canada [G. C-H., R. G. K., J. P. D., E. C. L.]

Activation of programmed cell death in cancer cells offers novel and potentially useful approaches to improving patient responses to conventional chemotherapy. X-linked inhibitor of apoptosis (XIAP), is the most potent member of the IAP gene family in terms of its ability to inhibit caspases and suppress apoptosis. In this study, we investigated the effect of XIAP down-regulation by antisense oligonucleotides (AS ODNs) on human non-small cell lung cancer (NIH-H460) growth in vitro and in vivo. In cultured H460 cells, G4 AS ODN was identified as the most potent compound. It down-regulated XIAP mRNA by 55% and protein levels up to 60% as determined by real-time quantitative reverse transcription-PCR and Western blotting, respectively, and induced 60% cell death. In contrast, the scrambled control ODN caused minimal XIAP loss and less than 10% cell death. Treatment with G4 AS ODN induced apoptosis as revealed by degradation of procaspase-3 and poly(ADP-ribose) polymerase proteins with significant nuclear DNA condensation and fragmentation. In addition, G4 AS ODNs sensitized H460 cells to the cytotoxic effects of doxorubicin, Taxol, vinorelbine, and etoposide. In animal models, administration of G4 AS ODN had significant sequence-specific inhibitory effects on H460 solid tumor establishment in a xenograft model. This antitumor activity was associated with an 85% down-regulation of XIAP protein in the tumors. In addition, the combination of 15 mg/kg G4 AS ODN with 5 mg/kg vinorelbine significantly delayed tumor establishment, more than either agent alone. These studies support the contention that XIAP is a viable target for cancer therapy in human non-small cell lung cancer.

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