Akademik Veri Yönetim Sistemi
MOLECULAR BIOLOGY, cilt.58, sa.6, ss.1280-1292, 2024 (SCI-Expanded)
Abstract—Cancer-multidrug resistance (MDR) is recognized as one of the barriers to the treatment of advanced hepatocellular carcinoma (HCC). We aim to inhibit ABCB1 overexpression observed in HCCMDR phenotypes with N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotides (ASOs). In this study, three ASOs (GalNAc-ASO1, GalNAc-ASO2, and GalNAc-ASO3) targeting ABCB1 mRNA and a scrambled-negative control (GalNAc-ASO4) were designed. Simulations of molecular docking were performed to determine the inhibitory efficacy of ASOs. GalNAc C3 phosphoramide ligand was added to the 5′-end of the ASO sequences, and phosphorothioate modifications were added to the DNA backbone. HepG2 cells were directly treated with different doses of GalNAc-ASOs conjugates. To evaluate the inhibitory effect of GalNAc-ASOs conjugates, the protein level of ABCB1 was measured by western blotting. The cell viability assays of GalNAc-ASO4 conjugates on HepG2 were evaluated by colorimetric-MTT and fluorometric-resazurin assays. Varying scrambled-negative control concentrations were applied to HepG2 for assessment of the cytotoxic effect of GalNAc-ASO4 conjugates, and it had no cytotoxic effect on cell viability up to 144 h. GalNAc-ASOs concentrations reducing ABCB1 protein expression after 72 h were detected by western blot. ASOs conjugated with the GalNAc ligand, which specifically targets the liver by binding to asialoglycoprotein receptors in hepatocyte cells, have the potential to increase the effect of anti-cancer therapies by reducing ABCB1 protein expression through gymnotic delivery to cells.