[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) phenotype due to overexpression of P-glycoprotein (Pgp). We have studied the effect of verapamil on Pgp expression levels in a cell line originating from acute myeloblastic leukemia and resistant to adriamycin, K562/ADR. In this line, the addition of 15 microM verapamil in the culture medium gives a 3-fold decrease of Pgp expression after 72 hours of treatment. Similar results have been obtained for two other MDR cell lines, which suggest that this phenomenon is not specific of a single model. The 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-transcriptional. We have also studied the effect of verapamil on the level of expression of mdr1 mRNAs in non-drug selected cells such as the HEL line (human acute myeloblastic leukemia) and the parental K562 line, which present a very low level of expression of Pgp, detectable only by PCR. In these lines, verapamil treatment has no effect on the level of expression of mdr1 mRNAs. The effect of verapamil is therefore restricted to drug-selected lines presenting high levels of Pgp expression. The impact of the negative regulation of Pgp expression on the MDR phenotype has been studied in the K562/ADR line. When the cells are treated for 72 h by verapamil, there is a decrease of resistance and an increase of intracellular accumulation of anticancer agents such as daunorubicin or vinblastine. Negative regulation of Pgp expression appears therefore as a possible strategy for MDR phenotype reversal. The effect of verapamil, whose molecular mechanism of action is being studied, could constitute a basis for this strategy.