RRC ID 77166
Author Matsumoto T, Jimi S, Hara S, Takamatsu Y, Suzumiya J, Tamura K.
Title Importance of inducible multidrug resistance 1 expression in HL-60 cells resistant to gemtuzumab ozogamicin.
Journal Leuk Lymphoma
Abstract 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.
Volume 53(7)
Pages 1399-405
Published 2012-7-1
DOI 10.3109/10428194.2012.656102
PMID 22242821
MeSH ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics* Aminoglycosides / pharmacology* Antibodies, Monoclonal, Humanized / pharmacology* Antineoplastic Agents / pharmacology Blotting, Western Butadienes / pharmacology Cell Survival / drug effects Cell Survival / genetics Dose-Response Relationship, Drug Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics* Flow Cytometry Gemtuzumab Gene Expression Regulation, Leukemic / drug effects* HL-60 Cells Humans Leukemia, Promyelocytic, Acute / genetics Leukemia, Promyelocytic, Acute / metabolism Leukemia, Promyelocytic, Acute / pathology MAP Kinase Kinase 1 / antagonists & inhibitors MAP Kinase Kinase 1 / metabolism MAP Kinase Kinase 2 / antagonists & inhibitors MAP Kinase Kinase 2 / metabolism Nitriles / pharmacology Reverse Transcriptase Polymerase Chain Reaction
IF 2.969
Human and Animal Cells HL60(RCB0041)