HUMAN MULTIDRUG-RESISTANT (MRP, P190) MYELOID-LEUKEMIA HL-60 ADR CELLS IN-VITRO - RESISTANCE TO THE MEVALONATE PATHWAY INHIBITOR LOVASTATIN/

Mevalonate pathway inhibitor lovastatin inhibited proliferation of hum an multidrug-resistant promyelocytic leukemia HL-60/ADR cells in vitro , with MRP-gene coded p190 mediated drug resistance, to a markedly les ser extent than that of the parental drug sensitive HL-60 cells and al so that of the other human multidrug resistant (MDR-1, P-glycoprotein) myeloid leukemia cell line HL-60/VCR. The sensitivity of the examined human leukemia cell lines to the cytostatic activity of lovastatin co rrelated approximately with the potential of lovastatin to induce the characteristic cell cycle alteration (i.e. the accumulation of lovasta tin-treated cells in the G(0)/G(1) phase of the cell cycle). The P-gly coprotein positive HL-60/VCR cells and the parental drug sensitive HL- 60 cells were more sensitive to this cell cycle alteration than the HL -60/ADR multidrug resistant leukemia cells with MRP drug resistance. L ovastatin (72 hours, 20 mu mol) induced apoptosis and cell necrosis in HL-60 cells, apoptosis but not cell necrosis in HL-60/VCR cells and n either apoptosis nor necrosis in HL-60/ADR cells.