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First published on February 25, 2008; DOI: 10.1124/mol.107.042010

0026-895X/08/7305-1568-1577$20.00
Mol Pharmacol 73:1568-1577, 2008

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Targeting MDR1 Gene: Synthesis and Cellular Study of Modified Daunomycin-Triplex-Forming Oligonucleotide Conjugates Able to Inhibit Gene Expression in Resistant Cell LinesFormula

Vérène Stierlé, Maria Duca, Ludovic Halby, Catherine Senamaud-Beaufort, Massimo L. Capobianco, Alain Laigle, Béatrice Jollès, and Paola B. Arimondo

Laboratoire de Biophysique Moléculaire, Cellulaire et Tissulaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7033, Université Pierre et Marie Curie-Paris 6, Paris, France (V.S., A.L., B.J.); Université Paris 13, Bobigny, France (V.S., A.L., B.J.); Laboratoire de Régulation et Dynamiques des Génomes Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5153, Muséum national d'Histoire naturelle USM0503 (M.D., L.H., C.S.-B., P.B.A.); Institut National de la Santé et de la Recherche Médicale UR565, Paris cedex 05, France (M.D., L.H., C.S.-B., P.B.A.); and Istituto per la Sintesi Organica e la Fotoreattività del Consiglio Nazionale delle Ricerche, Bologna, Italy (M.L.C.)

Reversal of the multidrug-resistant (MDR) phenotype is very important for chemotherapy success. In fact, the expression of the MDR1 gene-encoded P-glycoprotein (P-gp) actively expels antitumor agents such as daunomycin (DNM) out of the cells, resulting in drug resistance. We show that upon conjugation to triplex-forming oligonucleotides, it is possible to address DNM in resistant cells (MCF7-R and NIH-MDR-G185). The oligonucleotide moiety of the conjugate changes the cellular penetration properties of the antitumor agent that is no more the target of P-gp in resistant cells. We observe an accumulation of conjugated DNM in cells up to 72 h. For more efficient delivery in the cells' nuclei, transfectant agents must be used. In addition, the conjugate recognizes a sequence located in exon 3 of MDR1, and it inhibits its gene expression as measured both by Western blot and by reverse transcription-polymerase chain reaction.

Received for publication September 20, 2007.

Accepted for publication February 25, 2008.

Address correspondence to: Dr. Paola B. Arimondo, Unité Mixte de Recherche 5153 Centre National de la Recherche Scientifique-MNHN USM0503, Institut National de la Santé et de la Recherche Médicale UR565, 43 rue Cuvier, 75005 Paris, France. E-mail: arimondo{at}mnhn.fr




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