Differential effects of the MDR1 (multidrug resistance) gene-activating agents on protein kinase C: Evidence for redundancy of mechanisms of acquiredMDR in leukemia cells

Human leukemia cells may acquire MDR1/P-glycoprotein-mediated multidrug res istance (MDR) in the course of short-term (within hours) exposure to many s tress 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-tetradecanoy lphorbol 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 ceram ide, a lipid messenger known to mediate cellular effects of chemotherapeuti c drugs and TPA, activated the MDR1 gene and down-regulated PKC. These resu lts suggest that the MDR1 gene can be activated via the pathway(s) that req uires PKC activity as well as via bypass of PKC, The redundancy of signalin g pathways that regulate the acquisition of MDR should be taken into consid eration for prevention of secondary drug resistance in hematological malign ancies.