Differential effects of mitomycin D and doxorubicin on P-glycoprotein expression

Previous studies have demonstrated that mitomycin C (MMC) and other DNA cro ss-linking agents can suppress MDR1 (multidrug resistance 1) gene expressio n and subsequent functional P-glycoprotein (Pgp) expression, whereas doxoru bicin and other anthracyclines increase MDR1 gene expression. In the presen t study, with stably transfected Madin-Darby canine kidney C7 epithelial ce lls expressing a human Pgp tagged with green fluorescent protein under the proximal human MDR1 gene promoter, we demonstrated that MMC and doxorubicin have differential effects on Pgp expression and function. Doxorubicin caus ed a progressive increase in the cell-surface expression of Pgp and functio n. In contrast, MMC initially increased plasma membrane expression and func tion at a time when total cellular Pgp was constant and Pgp mRNA expression had been shown to be suppressed. This was followed by a rapid and sustaine d decrease in cell-surface expression at later times, presumably as a conse quence of the initial decrease in mRNA expression. These studies imply that there are at least two independent chemo-sensitive steps that can alter Pg p biogenesis: one at the level of mRNA transcription and the other at the l evel of Pgp trafficking. Understanding the combined consequences of these t wo mechanisms might lead to novel chemotherapeutic approaches to overcoming drug resistance in human cancers by altering either Bgp mRNA expression or trafficking to the membrane.