VERAPAMIL DECREASES P-GLYCOPROTEIN EXPRESSION IN MULTIDRUG-RESISTANT HUMAN LEUKEMIC-CELL LINES

We studied the effect of verapamil on Pgp expression (Pgp) in MDR huma n leukemia cell lines, K562/ADR and CEM VLB(100). In the K562/ADR cell line, addition of verapamil to the culture medium (15 mu M concentrat ion) resulted in a 3-fold decrease in Pgp expression after 72 hr expos ure. The effect of verapamil was reversible, and Pgp expression reache d the level of untreated controls 24 hr after discontinuation of verap amil. Similar results were obtained with the human vinblastine-resista nt cell line CEM VLB(100). On the contrary, no effect on Pgp expressio n was observed when the cells were treated with nifedipine or diltiaze m (2 other calcium-channel blockers), even at doses that inhibited cel l proliferation. The level of Pgp mRNA in the presence of verapamil wa s measured by Northern blot and was also decreased 2-fold (with the ma ximum reached within 24 hr), suggesting a transcriptional or post-tran scriptional mechanism for verapamil. We further established that the e ffect of verapamil on Pgp expression led to an increase in DNR and VLB accumulation and cytotoxicity. These results suggest that verapamil a cts specifically on Pgp expression in these drug-selected leukemic cel ls. The identification of a potentially novel mechanism of action may provide new insights as to how chemosensitization may be more effectiv ely applied in vivo. (C) 1994 Wiley-Liss, Inc.