Inhibition of MDR1 gene expression by H-87, a selective inhibitor of cAMP-dependent protein kinase.
N-[2-(p-bromocinnamylmethylamino) ethyl]-5-isoquinolinesulfonamide (H-87), a newly synthesized inhibitor of protein kinase A, significantly decreased the drug resistance of multidrug resistant human U937/M cells, mouse FM3A/M and P388/M cells. Northern blot analysis showed MDR1 gene expression was decreased in H-87-treated P388 M cells. H-87 inhibited the activity of MDR1 (multidrug resistance-1) promoter in a dose-dependent manner in transient expression assay. In contrast, the expression of c-raf-1 gene significantly enhanced the activity of MDR1 promoter. We therefore examined the effect of H-87 on MDR1 gene expression in c-raf-1 transfected CV-1 cells (CV-1/raf). A significant decrease in the level of MDR1 mRNA was observed after H-87 treatment of the CV-1/raf cells. These results suggest that inhibition of MDR1 gene expression by H-87 is associated with circumvention of drug resistance in MDR cells.
Kim
S H
SH
Department of Biochemistry, College of Medicine, Pusan National University, Korea.
Park
J I
JI
Chung
B S
BS
Kang
C D
CD
Hidaka
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D002478:Cells, Cultured / Q000187:drug effects; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D002522:Chlorocebus aethiops; D003078:Colchicine / Q000494:pharmacology; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008647:Mesocricetus; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014750:Vincristine; D014747:Vinblastine; D004317:Doxorubicin; D015500:Chloramphenicol O-Acetyltransferase; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D003078:Colchicine; D003630:Daunorubicin