Expression of the antisense cDNA for protein kinase C alpha attenuates resistance in doxorubicin-resistant MCF-7 breast carcinoma cells

Multidrug resistance is functionally associated with the expression of a plasma membrane energy-dependent drug efflux pump termed P-glycoprotein, the product of the mdr1 gene. Transfection of P-glycoprotein-expressing doxorubicin-resistant MCF-7 cells with an expression vector containing the cDNA fo...

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Bibliographic Details
Published inMolecular pharmacology Vol. 43; no. 6; pp. 858 - 862
Main Authors SHAKEEL AHMAD, GLAZER, R. I
Format Journal Article
LanguageEnglish
Published Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.06.1993
Subjects
Antineoplastic agents
ATP-Binding Cassette, Sub-Family B, Member 1
Biological and medical sciences
Breast Neoplasms - enzymology
Breast Neoplasms - pathology
Carrier Proteins - metabolism
Cell Death - drug effects
DNA, Antisense - genetics
Doxorubicin - pharmacology
Drug Resistance
Electrophoresis, Polyacrylamide Gel
General aspects
Humans
Immunoblotting
Medical sciences
Membrane Glycoproteins - metabolism
Pharmacology. Drug treatments
Phosphorylation
Protein Kinase C - genetics
Protein Kinase C - metabolism
Transfection
Tumor Cells, Cultured
Antineoplastic agent
Protein kinase C
Enzyme
Isozyme
Malignant tumor
In vitro
Mammary gland diseases
Regulation(control)
Complementary DNA
Multiple resistance
Established cell line
Reversibility
Anthracyclins
Mammary gland
Antisense DNA
Tumor cell
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Summary:Multidrug resistance is functionally associated with the expression of a plasma membrane energy-dependent drug efflux pump termed P-glycoprotein, the product of the mdr1 gene. Transfection of P-glycoprotein-expressing doxorubicin-resistant MCF-7 cells with an expression vector containing the cDNA for protein kinase C alpha in the antisense orientation reduces protein kinase C alpha levels and decreases total protein kinase C activity by 75%. This is accompanied by reduced phosphorylation of P-glycoprotein, a 2-fold increase in drug retention, and a 3-fold increase in doxorubicin cytotoxicity. These results provide further evidence that protein kinase C alpha can positively regulate multidrug resistance in MCF-7 cells through posttranslational phosphorylation of P-glycoprotein.
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ISSN:0026-895X
1521-0111