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 associated with an overexpression of ATP-binding cassette proteins [e.g. P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP)] and with decreased chemotherapeutic agent-induced apoptosis. In this study, we investigated whether MDR in cancer cells was associated with altered expression of genes regulating apoptosis using a drug sensitive human myeloid leukemia cell line (HL60), and its MDR sublines, overexpressing 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 level by reverse transcriptase-polymerase chain reaction (RT-PCR). We observed that the MDR cells either did not express or expressed a reduced level of the apoptosis promoters Fas, Bcl-x(s), and Bax, whereas expression of the apoptosis repressor Bcl-x, was increased. Both vincristine and anti-Fas monoclonal antibody induced apoptosis in HL60 cells but failed to do so in both MDR cell lines. These data suggest that acquired MDR in cancer cells, regardless of the type of overexpressed ABC transporter, may be associated with increased expression of antipeptidic genes and decreased expression of pro-apoptotic Genes.