Published online 17 August 2004
Nucleic Acids Research, Vol. 32 No. 14 © Oxford University Press 2004; all rights reserved
Inhibition of MDR1 gene expression by chimeric HNA antisense oligonucleotides
1 Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA, 2 Department of Life Science, Yongin University, Yongin 449-714, Korea and 3 Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Leuven, Belgium
* To whom correspondence should be addressed. Tel: +1 919 966 4383; Fax: +1 919 966 5640; Email: arjay{at}med.unc.edu
Correspondence may also be addressed to Dr Hyunmin Kang. Tel: +1 919 966 4343; Fax: +1 919 966 5640; Email: hkang{at}med.unc.edu
Received as resubmission June 13, 2004; Revised July 1, 2004; Accepted July 29, 2004
Hexitol nucleic acids (HNAs) are nuclease resistant and provide strong hybridization to RNA. However, there is relatively little information on the biological properties of HNA antisense oligonucleotides. In this study, we compared the antisense effects of a chimeric HNA ‘gapmer’ oligonucleotide comprising a phosphorothioate central sequence flanked by 5' and 3' HNA sequences to conventional phosphorothioate oligonucleotides and to a 2'-O-methoxyethyl (2'-O-ME) phosphorothioate ‘gapmer’. The antisense oligomers each targeted a sequence bracketing the start codon of the message of MDR1, a gene involved in multi-drug resistance in cancer cells. Antisense and control oligonucleotides were delivered to MDR1-expressing cells using transfection with the cationic lipid Lipofectamine 2000. The anti-MDR1 HNA gapmer was substantially more potent than a phosphorothioate oligonucleotide of the same sequence in reducing expression of P-glycoprotein, the MDR1 gene product. HNA and 2'-O-ME gapmers displayed similar potency, but a pure HNA antisense oligonucleotide (lacking the phosphorothioate ‘gap’) was ineffective, indicating that RNase H activity was likely required. Treatment with anti-MDR1 HNA gapmer resulted in increased cellular accumulation of the drug surrogate Rhodamine 123 that correlated well with the reduced cell surface expression of P-glycoprotein. Thus, HNA gapmers may provide a valuable additional tool for antisense-based investigations and therapeutic approaches.
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