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Verapamil decreases P‐glycoprotein expression in multidrug‐resistant human leukemic cell lines
Author(s) -
Muller Catherine,
Bailly JeanDenis,
Goubin Françoise,
Laredo Judith,
Jaffrézou JeanPierre,
Bordier Christine,
Laurent Guy
Publication year - 1994
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910560523
Subject(s) - verapamil , p glycoprotein , diltiazem , pharmacology , cell culture , k562 cells , northern blot , vinblastine , nicardipine , mechanism of action , nifedipine , in vivo , multiple drug resistance , gene expression , endocrinology , biology , in vitro , chemistry , medicine , leukemia , chemotherapy , calcium , drug resistance , biochemistry , gene , genetics , microbiology and biotechnology
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 (15μ 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 .