Selective inhibition of the effects of phorbol ester on doxorubicin resistance and P-glycoprotein by the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) in multidrug-resistant MCF-7/Dox human breast carcinoma cells

摘要: The possible regulation of the multidrug-resistant (MDR) phenotype and P-glycoprotein by protein kinase C (PKC) was investigated in doxorubicin (Dox)-resistant MCF-7 cell line (MCF-7/Dox). In a clonogenic assay, cells exposed to 100 nM phorbol 12-myristate 13-acetate (PMA) for 1 hr were about 3-fold more resistant Dox than alone. PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7, 30 microM) completely blocked PMA-induced effect, but did not reverse MDR phenotype. Complete down-regulation from MCF-7/Dox 24-hr preincubation with PMA alter degree resistance. Intracellular accumulation [14C]Dox decreased baseline 28 pmol/10(6) 15 presence PMA. reduced pretreatment H7. Following PMA, accumulated almost equal amounts absence or Cells PMA-treated colonies showed significantly higher levels expression when compared those control colonies. H7 affect basal level overexpression Upon stimulation (100 nM), alpha beta translocated membrane nucleus delta epsilon perinuclear nucleus, respectively. (30 inhibited translocations epsilon, whereas it only partially beta. These results suggest that appears resistance intracellular PKC-dependent manner induce increased cells. Differential effects on changes different isoforms may be involved growth drug processes as well expression.