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.