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An Antisense Oligonucleotide Targeted to Human Ku86 Messenger RNA Sensitizes M059K Malignant Glioma Cells to Ionizing Radiation, Bleomycin, and Etoposide but not DNA Cross-Linking Agents¹

Department of Oncology, Division of Radiation Oncology, Montreal General Hospital, McGill University, Montreal, Quebec, H3G 1A4 Canada [A. I. B., J-P. P., T. Y. K. C.]; Oncozyme Pharma, Inc., Montreal, Quebec, H1M 1V8 Canada [T. Y. K. C.]; Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, H3T 1E2 Canada [L. C. P]; and Department of Molecular Pharmacology, Isis Pharmaceuticals, Carlsbad, California 92008 [B. P. M.]

Ku is a heterodimer of M_r 70,000 and M_r 86,000 subunits. It binds with strong affinity to DNA ends and is indispensable for nonhomologous DNA end joining (NHEJ) and V(D)J recombination. In this study, we investigated whether down-regulation of the Ku86 gene, by 2'-O-methoxyethyl/uniform phosphorothioate chimeric antisense oligonucleotides (ASOs), increases the sensitivity of the DNA-protein kinase catalytic subunit (PKcs)-proficient human glioma cell line (M059K), and its isogenic DNA-PKcs-deficient counterpart (M059J), to ionizing radiation and anticancer drugs. Transfection of these cell lines with 200 nM Ku86 antisense ASOs was associated with a specific decrease in Ku86 mRNA levels (IC₅₀ <25 nM; n = 3) and a concomitant rapid decrease (<10% of control) in Ku86 protein expression. Moreover, transfection of M059K cells with Ku86 antisense ASOs markedly increased cell death after treatment with ionizing radiation, bleomycin, and etoposide. However, no sensitization to the DNA cross-linking agents chlorambucil and cisplatin was observed after Ku86 antisense transfection. As expected, transfection of M059J cells with Ku86 antisense ASOs did not result in any sensitization to ionizing radiation, bleomycin, or DNA cross-linking agents, but there was a 2-fold increase in sensitivity to etoposide. Thus, our results indicate that antisense ASOs targeted against Ku86 may increase the efficacy of radiotherapy and DNA-damaging agents in tumor treatment. Furthermore, Ku86 antisense ASOs may be used to create a temporal knockout in different human cell lines to further investigate the biological roles of Ku86.

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