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

We studied the effect of verapamil on Pgp expression (Pgp) in MDR human 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 concentration) resulted in a 3-fold decrease in Pgp expression after 72 hr exposure. The effect of verapamil was reversible, and Pgp expression reached the level of untreated controls 24 hr after discontinuation of verapamil. Similar results were obtained with the human vinblastine-resistant cell line CEM VLB(100). On the contrary, no effect on Pgp expression was observed when the cells were treated with nifedipine or diltiazem (2 other calcium-channel blockers), even at doses that inhibited cell proliferation. The level of Pgp mRNA in the presence of verapamil was measured by Northern blot and was also decreased 2-fold (with the maximum reached within 24 hr), suggesting a transcriptional or post-transcriptional mechanism for verapamil. We further established that the effect of verapamil on Pgp expression led to an increase in DNR and VLB accumulation and cytotoxicity. These results suggest that verapamil acts specifically on Pgp expression in these drug-selected leukemic cells. The identification of a potentially novel mechanism of action may provide new insights as to how chemosensitization may be more effectively applied in vivo. (C) 1994 Wiley-Liss, Inc.