TY - JOUR
T1 - Increased mdr-1/P-glycoprotein expression after treatment of human colon carcinoma cells with P-glycoprotein antagonists
AU - Herzog, Cynthia E.
AU - Tsokos, Maria
AU - Bates, Susan E.
AU - Fojo, Antonio T.
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1993/2/5
Y1 - 1993/2/5
N2 - We observed increased levels of mdr-1 mRNA and its protein product P-glycoprotein (Pgp) in the human colon carcinoma cell line, LS 180, and its drug-resistant sublines, LS 180-Ad50 and LS 180-Vb2, after treatment with the Pgp antagonists, verapamil, nifedipine, and cyclosporin A. Increases in mdr-1 RNA were observed within 8 h of the addition of the Pgp antagonists and continued to rise over time. Peak levels were attained after several weeks and were sustained for the duration of treatment up to several months, with a rapid decline in mdr-1 mRNA levels after removal of the Pgp antagonist. Corresponding changes in Pgp were demonstrated with addition and removal of the Pgp antagonists. Increased mdr-1 mRNA was also seen with two other calcium channel blockers, nicardipine and diltiazem, but not with the Pgp antagonists, quinidine and chlorpromazine. Treatment with verapamil or nifedipine was associated with electron microscopic changes consistent with increased differentiation and resulted in increased carcinoembryonic antigen expression, suggesting that the increase in mdr-1 expression was associated with the process of differentiation. Nuclear runoff experiments and inhibition of new RNA synthesis with actinomycin D treatment failed to detect an increase in mdr-1 transcription or stabilization of the mdr-1 mRNA suggesting that the effect of these agents is mediated post-transcriptionally within the nucleus.
AB - We observed increased levels of mdr-1 mRNA and its protein product P-glycoprotein (Pgp) in the human colon carcinoma cell line, LS 180, and its drug-resistant sublines, LS 180-Ad50 and LS 180-Vb2, after treatment with the Pgp antagonists, verapamil, nifedipine, and cyclosporin A. Increases in mdr-1 RNA were observed within 8 h of the addition of the Pgp antagonists and continued to rise over time. Peak levels were attained after several weeks and were sustained for the duration of treatment up to several months, with a rapid decline in mdr-1 mRNA levels after removal of the Pgp antagonist. Corresponding changes in Pgp were demonstrated with addition and removal of the Pgp antagonists. Increased mdr-1 mRNA was also seen with two other calcium channel blockers, nicardipine and diltiazem, but not with the Pgp antagonists, quinidine and chlorpromazine. Treatment with verapamil or nifedipine was associated with electron microscopic changes consistent with increased differentiation and resulted in increased carcinoembryonic antigen expression, suggesting that the increase in mdr-1 expression was associated with the process of differentiation. Nuclear runoff experiments and inhibition of new RNA synthesis with actinomycin D treatment failed to detect an increase in mdr-1 transcription or stabilization of the mdr-1 mRNA suggesting that the effect of these agents is mediated post-transcriptionally within the nucleus.
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M3 - Article
C2 - 8094079
AN - SCOPUS:0027500507
SN - 0021-9258
VL - 268
SP - 2946
EP - 2952
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 4
ER -