ALTERED EXPRESSION OF THE GENES REGULATING APOPTOSIS IN MULTIDRUG-RESISTANT HUMAN MYELOID-LEUKEMIA CELL-LINES OVEREXPRESSING MDR1 OR MRP GENE

Development of multidrug resistance (MDR) in cancer cells is associate d with an overexpression of ATP-binding cassette proteins [e.g. P-glyc oprotein (P-gp), multidrug resistance-associated protein (MRP)] and wi th decreased chemotherapeutic agent-induced apoptosis. In this study, we investigated whether MDR in cancer cells was associated with altere d expression of genes regulating apoptosis using a drug sensitive huma n myeloid leukemia cell line (HL60), and its MDR sublines, overexpress ing MRP (HL60/AR) or P-gp (HL60/taxol). Expression of apoptotic Genes was examined at the protein level by flow cytometry and at the mRNA le vel by reverse transcriptase-polymerase chain reaction (RT-PCR). We ob served that the MDR cells either did not express or expressed a reduce d level of the apoptosis promoters Fas, Bcl-x(s), and Bax, whereas exp ression of the apoptosis repressor Bcl-x, was increased. Both vincrist ine and anti-Fas monoclonal antibody induced apoptosis in HL60 cells b ut failed to do so in both MDR cell lines. These data suggest that acq uired MDR in cancer cells, regardless of the type of overexpressed ABC transporter, may be associated with increased expression of antipepti dic genes and decreased expression of pro-apoptotic Genes.