Abstract
P-glycoprotein (P-gp) is a membranous ATPase responsible for the multidrug resistance phenotype. The effect on P-gp-mediated transport of anthracyclines of cell irradiation in the presence of 2,2-diphenyl-5-[ N-1-( o-azidophenyl)ethylamino]valeronitrile (VP*), a photoactivable analogue of verapamil was studied in viable K562/ADR cells. The derivatives were daunorubicin (DNR), idarubicin (IDA), 8-( S)-fluoro-idarubicin (F-IDA), 2′-bromo-4′-epi-daunorubicin (Br-DNR) and pirarubicin (PIRA). It was observed that the irradiation in the presence of the verapamil analogue was unable to completely inhibit the P-gp-mediated efflux of anthracyclines and we estimated that P-gp retained 10–20% of its ability to pump these toxins. The ability of verapamil, DNR, IDA, F-IDA, Br-DNR and PIRA to inhibit the effect of VP* was studied. For this purpose, cells were irradiated in the presence of VP* and various concentrations of either verapamil or of one of the anthracyclines and then the P-gp functionality was checked by its ability to pump pirarubicin. It was observed that (i) the effect observed, when cells were irradiated in the presence of VP*, was completely blocked by the presence of verapamil; (ii) that anthracyclines are able to partially inhibit the VP* effect. This inhibition occurs at low concentration of anthracycline and depends on the nature of the derivative used. With those used in that study, after the photoirradiation of K562/ADR cells in the presence of VP* and anthracycline, P-gp has retained 50±5% of its functionality. The anthracycline concentration required for this inhibition is rather low, the total drug concentration yielding 50% of the effect ranged from 0.5 (Br-DNR) to 4 μM (F-IDA). The corresponding cytosolic concentrations are highly correlated with the values of K m determined previously.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.