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NF-κB decoy polyplexes decrease P-glycoprotein-mediated multidrug resistance in colorectal cancer cells

Cancer Gene Therapy volume 23, pages 149–155 (2016)Cite this article

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Abstract

Multidrug resistance (MDR), a major cause for chemotherapy failure, has been linked to upregulation of ATP-dependent membrane efflux systems that limit intracellular accumulation of cytotoxic anticancer agents. P-glycoprotein (P-gp) encoded by the human ABCB1 gene was the first efflux transporter identified to contribute to MDR. ABCB1 gene expression is correlated with constitutive activation of the NF-κB signaling pathway in tumor cells. The objective of this research is to modulate P-gp activity in colon cancer cells using NF-κB decoy oligodeoxynucleotides (ODNs) that are effectively delivered into the nucleus of colorectal cancer cells by self-assembling nonviral nanoparticles comprising the novel poly[N-(2-hydroxypropyl)methacrylamide]-poly(N,N-dimethylaminoethylmethacrylate) diblock copolymer (pHPMA-b-pDMAEMA). Ethidium bromide intercalation and gel retardation assays demonstrated high DNA condensation capacity of pHPMA-b-pDMAEMA. Nanoparticles prepared with and without decoy ODNs did not significantly compromise cellular safety at N/P ratios ⩽4. Transfection efficiency of pHPMA-b-pDMAEMA polyplexes (N/P=4) in Caco-2 cells was comparable to TurboFect transfection standard, resulting in a 98% reduction in P-gp protein levels. As a pharmacodynamic consequence, intracellular accumulation of the P-gp substrate Rhodamine123 significantly increased by almost twofold. In conclusion, NF-κB ODN polyplexes fabricated with pHPMA-b-pDMAEMA polymer effectively reduced P-gp-mediated efflux activity in Caco-2 cells, suggesting successful interference with NF-κB-binding sites in the promoter region of the ABCB1 gene.

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Acknowledgements

This research was supported in part by a predoctoral fellowship from the Egyptian Ministry of Higher Education awarded to Noura H Abd Ellah.

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Authors and Affiliations

  1. James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA

    N H Abd Ellah & G M Pauletti

  2. Faculty of Pharmacy, Assiut University, Assiut, Arab Republic of Egypt

    N H Abd Ellah, M M Elmahdy, G N Fetih & E A Ibrahim

  3. Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA

    L Taylor & N Ayres

  4. Division of General and Thoracic Surgery and Reproductive Sciences, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    H N Jones

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  1. N H Abd Ellah
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  2. L Taylor
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Correspondence to G M Pauletti.

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Abd Ellah, N., Taylor, L., Ayres, N. et al. NF-κB decoy polyplexes decrease P-glycoprotein-mediated multidrug resistance in colorectal cancer cells. Cancer Gene Ther 23, 149–155 (2016). https://doi.org/10.1038/cgt.2016.17

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  • DOI: https://doi.org/10.1038/cgt.2016.17

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