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Functional comparison of single- and double-stranded mdr1 antisense oligodeoxynucleotides in human ovarian cancer
Veronika Jekerle1, Matthias U Kassack, Raymond M Reilly
1Pharmaceutical Institute, University of Bonn, Germany.
Purpose:
P-glycoprotein mediated multidrug resistance presents a major obstacle in the successful therapeutic treatment of solid tumors such as ovarian cancer. Among the more promising techniques used to overcome multidrug resistance in ovarian cancer, is the transcriptional suppression of P-glycoprotein by antisense oligodeoxynucleotides (ODNs). To design more potent antisense ODNs, we explored the concept that double-stranded antisense ODNs may offer advantages in stability and potency over single-stranded in analogy to double-stranded siRNA.
Method:
Single-stranded phosphorothioate antisense ODNs against the human mdr1 gene were compared to the duplex of the active antisense and sense sequence of the same length. Concentration dependant effects on P-glycoprotein (Pgp) expression and functionality were quantitatively compared in the Pgp overexpressing ovarian cancer cell line A2780/Adr and its parental cell line A2780. Antisense ODNs were (111)Indium- and fluorescein isothiocyanate-conjugated for stability, cellular uptake and nuclear localization studies. Duplex formation significantly enhanced transcriptional inhibition of Pgp surface expression and functionality. Cellular uptake and distribution to the nucleus was improved when utilized as double-stranded DNA.
Conclusion:
Novel findings from this study suggest that double-stranded antisense ODNs more effectively inhibit target protein expression and consequently enhance chemoresponsiveness through improvements in cellular uptake and distribution to the nucleus.
Insights
Double-stranded antisense oligodeoxynucleotides (ODNs) show enhanced potency against P-glycoprotein (Pgp) in ovarian cancer cells. This approach improves cellular uptake and nuclear distribution, offering a promising strategy to overcome multidrug resistance.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Development
Background:
- P-glycoprotein (Pgp) mediates multidrug resistance in solid tumors, particularly ovarian cancer, hindering effective therapy.
- Antisense oligodeoxynucleotides (ODNs) offer a potential strategy to suppress Pgp transcription and overcome this resistance.
- The development of more potent antisense ODNs is crucial for improving therapeutic outcomes.
Purpose of the Study:
- To investigate the potential advantages of double-stranded antisense ODNs over single-stranded ODNs for inhibiting P-glycoprotein.
- To compare the stability, potency, and cellular mechanisms of double-stranded versus single-stranded antisense ODNs targeting the mdr1 gene.
- To evaluate the impact of double-stranded antisense ODNs on Pgp expression, function, and chemoresponsiveness in ovarian cancer cells.
Main Methods:
- Comparison of single-stranded phosphorothioate antisense ODNs with their corresponding double-stranded duplexes (antisense/sense) against the human mdr1 gene.
- Quantitative assessment of Pgp expression and functionality in Pgp-overexpressing (A2780/Adr) and parental (A2780) ovarian cancer cell lines.
- Utilized (111)Indium- and fluorescein isothiocyanate-conjugated ODNs for cellular uptake and nuclear localization studies.
Main Results:
- Double-stranded antisense ODNs significantly enhanced the transcriptional inhibition of Pgp surface expression compared to single-stranded ODNs.
- The functionality of P-glycoprotein was more effectively inhibited by double-stranded antisense ODNs.
- Cellular uptake and nuclear distribution of the ODNs were improved when they were utilized in a double-stranded DNA formation.
Conclusions:
- Double-stranded antisense ODNs represent a more effective approach for inhibiting target protein expression, specifically P-glycoprotein.
- This enhanced inhibition leads to improved chemoresponsiveness in ovarian cancer cells.
- The improved cellular uptake and nuclear distribution of double-stranded antisense ODNs contribute to their increased potency and therapeutic potential.
