Abstract
ABSTRACTWe 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.
Highlights
P-glycoprotein (P-gp) encoded by the human MDR1/ABCB1 gene, is a cell membrane glycoprotein with a molecular weight of 170 kDa first discovered in drug-resistant Chinese hamster ovary cells in 1976 by Juliano et al(Juliano and Ling, 1976)
We investigate the biological characteristics of AqMDRs formed by intercellular P-gp transfer and whether AqMDRs can form stable drug-resistant strains
Observation of AqMDR cells by laser confocal microscopy:BIU-87 and BIU-87/DOX cells were cocultured in a transwell system for 24 h, 48 h, 72 h, or 96 h
Summary
P-glycoprotein (P-gp) encoded by the human MDR1/ABCB1 gene, is a cell membrane glycoprotein with a molecular weight of 170 kDa first discovered in drug-resistant Chinese hamster ovary cells in 1976 by Juliano et al(Juliano and Ling, 1976). MDR is common in bladder tumors, and expression of the MDR1 gene can be detected in bladder cancer tissues from more than 75% of patients (Featherstone et al, 2005). The expression of P-gp was negatively correlated with the prognosis of bladder cancer (Hoffmann et al, 2010). Our previous studies (Zhou et al, 2013) have shown that P-gp can be transferred from the resistant bladder cancer cell line BIU-87/DOX to the sensitive strain BIU-87, which is not resistant to doxorubicin(DOX), providing the first evidence that this "non-genetic" acquired MDR mechanism exists among bladder cancer cells
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