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Nucleic Acids Research 2006 34(2):734-744; doi:10.1093/nar/gkj473
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Published online 30 January 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Growth inhibition and apoptosis induced by daunomycin-conjugated triplex-forming oligonucleotides targeting the c-myc gene in prostate cancer cells

Sara Napoli, Umberto Negri1, Federico Arcamone1, Massimo L. Capobianco1, Giuseppina M. Carbone and Carlo V. Catapano*

Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland Via Vela 6, Bellinzona, CH-6500 Switzerland 1ISOF-CNR Via Gobetti 101, Bologna, 40129 Italy

*To whom correspondence should be addressed at Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland. Tel: +41 91 820 0365; Fax: +41 91 820 0397; Email: carlo.catapano{at}irb.unisi.ch

Received December 1, 2005. Revised January 11, 2006. Accepted January 11, 2006.

Covalent attachment of intercalating agents to triplex-forming oligonucleotides (TFOs) is a promising strategy to enhance triplex stability and biological activity. We have explored the possibility to use the anticancer drug daunomycin as triplex stabilizing agent. Daunomycin-conjugated TFOs (dauno-TFOs) bind with high affinity and maintain the sequence-specificity required for targeting individual genes in the human genome. Here, we examined the effects of two dauno-TFOs targeting the c-myc gene on gene expression, cell proliferation and survival. The dauno-TFOs were directed to sequences immediately upstream (dauno-GT11A) and downstream (dauno-GT11B) the major transcriptional start site in the c-myc gene. Both dauno-TFOs were able to down-regulate promoter activity and transcription of the endogenous gene. Myc-targeted dauno-TFOs inhibited growth and induced apoptosis of prostate cancer cells constitutively expressing the gene. Daunomycin-conjugated control oligonucleotides with similar sequences had only minimal effects, confirming that the activity of dauno-TFOs was sequence-specific and triplex-mediated. To test the selectivity of dauno-TFOs, we examined their effects on growth of normal human fibroblasts, which express low levels of c-myc. Despite their ability to inhibit c-myc transcription, both dauno-TFOs failed to inhibit growth of normal fibroblasts at concentrations that inhibited growth of prostate cancer cells. In contrast, daunomycin inhibited equally fibroblasts and prostate cancer cells. Thus, daunomycin per se did not contribute to the antiproliferative activity of dauno-TFOs, although it greatly enhanced their ability to form stable triplexes at the target sites and down-regulate c-myc. Our data indicate that dauno-TFOs are attractive gene-targeting agents for development of new cancer therapeutics.

Correspondence may also be addressed to Giuseppina M. Carbone. Tel: +41 91 820 0366; Fax: +41 91 820 0397; Email: pina.carbone{at}irb.unisi.ch


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