u-0126 and Leukemia--Promyelocytic--Acute

Resistance to gemtuzumab ozogamicin (GO) hampers the effective treatment of refractory acute myeloid leukemia (AML). To clarify the mechanism of resistance to GO, HL-60 cells were persistently exposed to GO in order to establish GO-resistant HL-60 (HL-60/GOR) cells. Multidrug resistance 1 (MDR-1) was strongly expressed in HL-60/GOR cells, but not in HL-60 cells. Although withdrawal of GO after the chronic exposure of HL-60/GOR cells to this compound gradually decreased MDR-1 expression to trace levels, reintroducing GO restored high MDR-1 expression in HL-60/GOR cells, but not in HL-60 cells. These results indicate that HL-60/GOR cells acquired the ability to induce MDR-1 expression in response to GO. U0126, a MEK1/2 inhibitor, prevented GO-inducible MDR-1 expression and abrogated GO resistance in HL-60/GOR cells. These results suggest that in the clinical use of GO, inducible MDR-1 expression in tumor cells should be investigated before treatment with GO. If the cells are positive then MEK1/2 inhibitors may be effective in overcoming resistance to GO.

Topics: Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Butadienes; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Flow Cytometry; Gemtuzumab; Gene Expression Regulation, Leukemic; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Nitriles; Reverse Transcriptase Polymerase Chain Reaction