Importance of inducible multidrug resistance 1 expression in HL-60 cells resistant to gemtuzumab ozogamicin.

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.

• Authors: Taichi Matsumoto, Shiro Jimi, Shuuji Hara, Yasushi Takamatsu, Junji Suzumiya, Kazuo Tamura
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 53 Issue 7 Pg. 1399-405 (Jul 2012) ISSN: 1029-2403 [Electronic] United States
• PMID: 22242821 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Aminoglycosides
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Butadienes
• Nitriles
• U 0126
• Gemtuzumab
• MAP2K2 protein, human
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human

Topics

• 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, genetics)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects, genetics)
• Flow Cytometry
• Gemtuzumab
• Gene Expression Regulation, Leukemic (drug effects)
• HL-60 Cells
• Humans
• Leukemia, Promyelocytic, Acute (genetics, metabolism, pathology)
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, metabolism)
• Nitriles (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction