Aptamer inhibits P-glycoprotein efflux function via the Wnt/β-catenin signaling pathway
- Biochem Biophys Res Commun. 2025 May 26:760:151709. doi: 10.1016/j.bbrc.2025.151709.
- 1. School of Life Science, Beijing Institute of Technology, Beijing, 100081, China. Electronic address: [email protected].
- 2. School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
- 3. People's Liberation Army Strategic Support Force Characteristic Medical Center, Beijing, 100101, China. Electronic address: [email protected].
- 4. Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, Shandong, China. Electronic address: [email protected].
Inhibiting permeability glycoprotein (P-gp) efflux is a strategy to enhance drug efficacy or overcome multidrug resistance in tumors. However, whether P-gp aptamer (APTP-gp, an 81 bp ssDNA) inhibits P-gp efflux is unknown. Increased Rho123 uptake was observed in the rat brain and intestine. Bidirectional transport of Rho123 indicated that 100 nM of APTP-gp inhibited P-gp activity with inhibition ratios of 75.0 % in Caco-2 and 60.5 % in hCMEC/D3 cells. The apparent permeability coefficients (Papp) from the apical (AP) to basolateral (BL) sides significantly increased by 129.4 % in Caco-2 and 8.0 % in hCMEC/D3 cells, respectively. The Papp from the BL→AP sides in the two cell lines decreased. P-gp mRNA and protein expression in the rat ileum, brain, and two cell lines markedly decreased following APTP-gp exposure. APTP-gp downregulated Wnt3, pho-Dvl2, β-catenin expression and decreased the ratio of pho-GSK-3β to GSK-3β in the rat ileum and brain. Molecular docking analysis suggested that APTP-gp interact with Wnt/β-catenin signaling pathway proteins at various amino acid sites. The present study reports a novel a novel nucleic acid-based P-gp inhibitor, which may benefit for enhancing drug efficacy or overcome multidrug resistance in clinical application.