STEROID-TRANSPORT, ACCUMULATION, AND ANTAGONISM OF P-GLYCOPROTEIN IN MULTIDRUG-RESISTANT CELLS

According to multiple reports, progesterone is not transported by P-gl ycoprotein (Pgp), which mediates multidrug resistance through active d rug efflux. However, progesterone has been shown to block Pgp-mediated efflux of other drugs. To extend these observations, and to examine t he effect of modulating Pgp phosphorylation, the accumulation of proge sterone and 14 other steroids in untreated and calphostin C-treated mu ltidrug-resistant human colon carcinoma SW620 Ad300 cells was compared to the accumulation in parental SW620 cells. The accumulation of prog esterone in untreated multidrug resistant cells expressing Pgp was not reduced compared to parental cells. However, the accumulation of more hydrophilic steroids was reduced by as much as 50%. Progesterone and progesterone-like compounds, however, were potent inhibitors of Pgp-me diated vinblastine efflux; increased antagonism correlated with increa sed steroid hydrophobicity. Treatment with calphostin C, a PKC inhibit or which decreases Pgp phosphorylation, increased progesterone efflux, modulated Pgp antagonism by steroids, and inhibited photoaffinity lab eling of Pgp by progesterone. These results extend previous observatio ns that Pgp can mediate the transport of, and be antagonized by, a var iety of steroids and that these properties vary with both a steroid's hydrophobicity and the phosphorylated state of Pgp.