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Research ArticleArticle

A Single Decoy Oligodeoxynucleotides Targeting Multiple Oncoproteins Produces Strong Anticancer Effects

Huanhuan Gao, Jiening Xiao, Qiang Sun, Huixian Lin, Yunlong Bai, Long Yang, Baofeng Yang, Huizhen Wang and Zhiguo Wang
Molecular Pharmacology November 2006, 70 (5) 1621-1629; DOI: https://doi.org/10.1124/mol.106.024273
Huanhuan Gao
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Jiening Xiao
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Qiang Sun
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Huixian Lin
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Yunlong Bai
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Long Yang
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Baofeng Yang
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Huizhen Wang
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Zhiguo Wang
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Abstract

Cancer in general is a multifactorial process. Targeting a single factor may not be optimal in therapy, because single agents are limited by incomplete efficacy and dose-limiting adverse effects. Combination pharmacotherapy or “drug cocktail” therapy has value against many diseases, including cancers. We report an innovative decoy oligodeoxynucleotide (dODN) technology that we term complex decoy oligodeoxynucleotide (cdODNs) in which multiple cis elements are engineered into single dODNs attacking multiple target transcription factors, mimicking the drug cocktail approach. We designed dODNs targeting NF-κB, E2F, and Stat3 separately and a cdODN targeting NF-κB, 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-κB, E2F, and Stat3 together demonstrated enhancement of efficacy of more than 2-fold and increases in potency of 2 orders of magnitude compared with each of the dODNs or the combination of all three dODNs. The cdODN also showed earlier onset and longer-lasting action. 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 reverse transcription-polymerase chain reaction revealed that the cdODNs knocked down expression 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-target” therapy for a broad range of human cancers.

Footnotes

  • This work was supported in part by the Fonds de la Recherche de l'Institut de Cardiologie de Montreal (to Z.W.).

  • ABBREVIATIONS: dODN, decoy oligodeoxynucleotide; ODN, oligodeoxynucleotide; TF, transcription factor; sdODN, simplex decoy ODN (a decoy ODN containing only one cis element); cdODN, complex decoy ODN (a decoy ODN containing multiple cis elements); RT, room temperature; EMSA, electrophoretic mobility shift assay; PBS, phosphate-buffered saline; SSC, standard saline citrate; PI, propidium iodide; FITC, fluorescein isothiocyanate; NES, cdODN with three cis elements NF-κB, E2F, and Stat3; N+E+S, coapplication of NF-κB1, E2F1, and Stat31; NC, negative control; NF-κB, nuclear factor κB.

    • Received March 8, 2006.
    • Accepted August 25, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (5)
Molecular Pharmacology
Vol. 70, Issue 5
1 Nov 2006
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Research ArticleArticle

A Single Decoy Oligodeoxynucleotides Targeting Multiple Oncoproteins Produces Strong Anticancer Effects

Huanhuan Gao, Jiening Xiao, Qiang Sun, Huixian Lin, Yunlong Bai, Long Yang, Baofeng Yang, Huizhen Wang and Zhiguo Wang
Molecular Pharmacology November 1, 2006, 70 (5) 1621-1629; DOI: https://doi.org/10.1124/mol.106.024273

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Research ArticleArticle

A Single Decoy Oligodeoxynucleotides Targeting Multiple Oncoproteins Produces Strong Anticancer Effects

Huanhuan Gao, Jiening Xiao, Qiang Sun, Huixian Lin, Yunlong Bai, Long Yang, Baofeng Yang, Huizhen Wang and Zhiguo Wang
Molecular Pharmacology November 1, 2006, 70 (5) 1621-1629; DOI: https://doi.org/10.1124/mol.106.024273
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