期刊
BLOOD
卷 128, 期 14, 页码 1845-1853出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-07-660506
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资金
- National Cancer Institute, National Institutes of Health [R01-CA160979]
- When Everyone Survives Foundation (Duluth, GA)
- Gabrielle's Angel Foundation (New York, NY)
- Lymphoma Research Foundation (New York, NY)
- DeGregorio Family Foundation (Pleasantville, NY)
- Kittredge Foundation
- Brent Leahey Fund
- National Institute of General Medical Sciences [T32GM007753, F30 CA165740-01]
- [Millennium Nucleus-P-07-011-F]
- [FONDAP-15150012]
The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron), an antimicrobial approved by the US Food and Drug Administration, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130, which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone for Pneumocystis prophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically accessible STAT3 inhibitor with evidence of anticancer efficacy in both animal models and humans.
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