title: NF-κB decoy polyplexes decrease P-glycoprotein-mediated multidrug resistance in colorectal cancer cells.
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.
authors.affiliation: James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.|Faculty of Pharmacy, Assiut University, Assiut, Arab Republic of Egypt.
authors.forename: N H
authors.initials: NH
authors.lastname: Abd Ellah
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Taylor
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ayres
authors.affiliation: Faculty of Pharmacy, Assiut University, Assiut, Arab Republic of Egypt.
authors.forename: M M
authors.initials: MM
authors.lastname: Elmahdy
authors.affiliation: Faculty of Pharmacy, Assiut University, Assiut, Arab Republic of Egypt.
authors.forename: G N
authors.initials: GN
authors.lastname: Fetih
authors.affiliation: Division of General and Thoracic Surgery and Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: H N
authors.initials: HN
authors.lastname: Jones
authors.affiliation: Faculty of Pharmacy, Assiut University, Assiut, Arab Republic of Egypt.
authors.forename: E A
authors.initials: EA
authors.lastname: Ibrahim
authors.affiliation: James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Pauletti
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D009838:Oligodeoxyribonucleotides / Q000235:genetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides