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S Ahmad and RI Glazer
Department of Pharmacology, Georgetown University Medical Center, Washington, D.C. 20007.
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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