Differential effects of the MDR1 (multidrug resistance) gene-activating agents on protein kinase C: evidence for redundancy of mechanisms of acquired MDR in leukemia cells.
Human leukemia cells may acquire MDR1/P-glycoprotein-mediated multidrug resistance (MDR) in the course of short-term (within hours) exposure to many stress stimuli. This effect is thought to be associated with the activity of protein kinase C (PKC) (Chaudhary, Roninson, 1992. 1993). However, we show here that cytosine beta-D-arabinofuranoside (Ara C) and 12-O-tetradecanoylphorbol 13-acetate (TPA), agents that activated the MDR1 gene in the H9 T-cell leukemia line, caused different effects on PKC. Namely, TPA activated PKC whereas Ara C was without the effect. Furthermore, cell permeable ceramide, a lipid messenger known to mediate cellular effects of chemotherapeutic drugs and TPA, activated the MDR1 gene and down-regulated PKC. These results suggest that the MDR1 gene can be activated via the pathway(s) that requires PKC activity as well as via bypass of PKC. The redundancy of signaling pathways that regulate the acquisition of MDR should be taken into consideration for prevention of secondary drug resistance in hematological malignancies.
Shtil
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AA
Institute of Carcinogenesis, N. Blokhin Cancer Center, Moscow, Russia. shtilaa@yahoo.com
Ktitorova
O V
OV
Kakpakova
E S
ES
Holian
O
O
D002518:Ceramides / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D019450:Genes, MDR / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000473:pathology; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D015290:Second Messenger Systems; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D002518:Ceramides; D003561:Cytarabine; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate