Received for publication March 9, 2006.
Revised August 25, 2006.
Accepted for publication August 25, 2006.

A single decoy oligodeoxynucleotides targeting multiple oncoproteins produces strong anti-cancer effects

Abstract

A cancer in general is a multifactorial process. Targeting a single factor may not be optimal in therapy for single agents are limited by incomplete efficacy and dose-limiting adverse effects. Combination pharmacotherapy or 'drug cocktail' therapy has found its appealing value against many diseases including cancers. We report an innovative decoy oligodeoxynucleotides (dODN) technology that we term complex decoy oligodeoxynucleotides (cdODNs) in which multiple cis- elements are engineered into single dODNs directed attacking multiple target transcription factors, mimicking 'drug cocktail' approach. We designed dODNs targeting NF-B, E2F and Stat3 separately, and a cdODN targeting NF-B, E2F and Stat3 concomitantly. We evaluated effects of this cdODN on expression of cancer-related genes, viability of human cancer cell lines and in vivo tumor growth in nude mice. The cdODN targeting all NF-B, E2F and Stat3 together demonstrated more than two-fold enhancement of the efficacy and two orders of magnitude increases in potency, compared with each of the dODNs or the combination of all three dODNs. The cdODN also showed earlier onset and longer-lasing actions. Most strikingly, the cdODN acquired the ability to attack multiple molecules critical to cancer progression via multiple mechanisms leading to elimination of regression. Real-time RT-PCR revealed that the cdODNs knocked down expressions of the genes regulated by the target transcription factors. The cdODN strategy offers resourceful combinations of varying cis- elements for concomitantly targeting multiple molecules in cancer biological processes and opens the door to 'one drug-multiple targets' therapy for a broad range of human cancers.

Key words: Stat activated transcriptional events, NFkappaB, DNA binding sites, Regulation - transcriptional, Nucleoside/Nucleotide derivatives, Oncogenes, Transcription targets

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