Intercellular transfer of P-glycoprotein mediates the formation of stable multi-drug resistance in human bladder cancer BIU-87 cells

Abstract

We investigated the biological characteristics of acquired drug-resistant cells (AqMDRs) formed by intercellular P-glycoprotein (P-gp) transfer and whether AqMDRs can form stable drug-resistant strains. Drug-sensitive BIU-87 cells were co-cultured with doxorubicin (DOX)-resistant derivative BIU-87/DOX cells in transwell chambers for up to 96 h. The presence of P-gp in recipient cell membranes (AqMDRs) was detected by confocal microscopy, CCK-8, western blot, and RT-PCR were used to detect resistance index (RI), P-gp expression and MDR1 mRNA expression in AqMDRs after 0, 4, 8, 16, and 20 passages and frozen/resuscitated twentieth generation AqMDRs. There was an increase in P-gp transfer with longer co-culture times of drug-resistant and sensitive strains. Without DOX, although the AqMDR numbers increased with each passage, the RI and P-gp expression decreased gradually, and the expression level of MDR1 mRNA did not change significantly. With DOX, the RI and P-gp expression increased slightly, and the MDR1 mRNA expression level gradually increased to the BIU-87/DOX level. AqMDRs can grow stably at drug concentrations slightly higher than the IC50 of sensitive strains, which sensitive strains cannot survive. P-gp transfer between cells gradually increases with longer co-culturing of drug-resistant and sensitive strains. The drug resistance of AqMDRs decreases without drug intervention, but with drug intervention, cells can maintain resistance and gradually develop into stable drug-resistant cells. This article has an associated First Person interview with the first author of the paper.

Keywords

• Bladder cancer
• Multidrug resistance
• P-glycoprotein
• Intercellular transfer