Relation between the Induction of MDR1, a Multidrug Resistance Gene in Tumor Cells, and Apoptosis

Gene MDR1coding for P-glycoprotein belongs to a group of genes responsible for cell defense. The overexpression of this gene determines the resistance of tumor cells to a series of chemotherapeutic drugs known as multidrug resistance. Many chemotherapeuticals induce both the apoptosis and transcriptional activity of the MDR1gene in tumor cells. It is not known, however, how these two processes are associated with each other. In order to elucidate a possible link between them, we have studied the sphyngomyelinic pathway of signal transduction. This pathway is activated in response to various stress factors and includes the hydrolysis of sphyngomyelin of cytoplasmic membrane resulting in an accumulation of intracellular ceramide, which activates cascades of enzymatic reactions leading to various cell responses, including apoptosis. C2ceramide (N-acetyl-D-sphyngosine) and cytosar (1β-D-arabinosylcytosine, or ara C) were used to induce the sphyngomyelinic pathway. Their effects on human hemoblastosis cell lines (K562 and H9 cell lines) were examined. C2ceramide and ara C induced apoptosis in both cell lines over an 18-h incubation. C2ceramide also induced an increase in the expression of the gene MDR1in both cell lines, while ara C increased the activity of the gene MDR1only in H9 cells. The results obtained provide evidence for the contribution of ceramide-mediated signal pathway to the control of MDR1activity.