PHARMACOLOGICAL CONTROL OF P-GLYCOPROTEIN EXPRESSION

Calcium channel inhibitors, such as verapamil, have been identified as having the ability to modulate the multidrug-resistant (MDR) phenotyp e due to overexpression of P-glycoprotein (Pgp). We have studied the e ffect of verapamil on Pgp expression levels in a cell line originating from acute myeloblastic leukemia and resistant to adriamycin, K562/AD R. In this line, the addition of 15 mu M verapamil in the culture medi um gives a 3-fold decrease of Pgp expression after 72 hours of treatme nt. Similar results have been obtained for two other MDR cell lines, w hich suggest that this phenomenon is not specific of a single model. T he level of mdr1 mRNAs is decreased in the presence of verapamil (with a maximum effect obtained at the 24th hour), which suggests that the mechanism of action of verapamil is transcriptional and/or post-transc riptional. We have also studied the effect of verapamil on the level o f expression of mdr1 mRNAs in non-drug selected cells such as the HEL line (human acute myeloblastic leukemia) and the parental K562 line, w hich present a very low level of expression of Pgp, detectable only by PCR. In these lines, verapamil treatment has no effect on the level o f expression of mdr1 mRNAs. The effect of verapamil is therefore restr icted to drug-selected lines presenting high levels of Pgp expression. The impact of the negative regulation of Pgp expression on the MDR ph enotype has been studied in the K562/ADR line. When the cells are trea ted for 72 h by verapamil, there is a decrease of resistance and an in crease of intracellular accumulation of anticancer agents such as daun orubicin or vinblastine. Negative regulation of Pgp expression appears therefore as a possible strategy for MDR phenotype reversal. The effe ct of verapamil, whose molecular mechanism of action is being studied, could constitute a basis for this strategy.