Cabozantinib is selectively cytotoxic in acute myeloid leukemia cells with FLT3-internal tandem duplication (FLT3-ITD)
Journal
Cancer Letters
Journal Volume
376
Journal Issue
2
Pages
218
Date Issued
2016
Author(s)
Lu J.-W
Wang A.-N
Liao H.-A
Abstract
Cabozantinib is an oral multikinase inhibitor that exhibits anti-tumor activity in several cancers. We found that cabozantinib was significantly cytotoxic to MV4-11 and Molm-13 cells that harbored FLT3-ITD, resulting in IC50 values of 2.4 nM and 2.0 nM, respectively. However, K562, OCI-AML3 and THP-1 (leukemia cell lines lacking FLT3-ITD) were resistant to cabozantinib, showing IC50 values in the micromolar range. Cabozantinib arrested MV4-11 cell growth at the G0/G1 phase within 24 h, which was associated with decreased phosphorylation of FLT3, STAT5, AKT and ERK. Additionally, cabozantinib induced MV4-11 cell apoptosis in a dose-dependent manner (as indicated by annexin V staining and high levels of cleaved caspase 3 and PARP-1), down-regulated the anti-apoptotic protein survivin and up-regulated the pro-apoptotic protein Bak. Thus, cabozantinib is selectively cytotoxic to leukemia cells with FLT3-ITD, causing cell-cycle arrest and apoptosis. In mouse xenograft model, cabozantinib significantly inhibited MV4-11 and Molm-13 tumor growth at a dosage of 10 mg/kg and showed longer survival rate. Clinical trials evaluating the efficacy of cabozantinib in acute myeloid leukemia (AML) with FLT3-ITD are warranted. ? 2016 Elsevier Ireland Ltd.
SDGs
Other Subjects
cabozantinib; caspase 3; CD135 antigen; cyclin dependent kinase inhibitor; cyclin E; mitogen activated protein kinase; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; protein Bak; protein kinase B; protein p27; STAT5 protein; survivin; anilide; antineoplastic agent; apoptosis regulatory protein; cabozantinib; CD135 antigen; FLT3 protein, human; protein kinase inhibitor; pyridine derivative; acute myeloblastic leukemia; animal cell; animal model; animal tissue; antineoplastic activity; antiproliferative activity; apoptosis; Article; cancer inhibition; cancer survival; cell cycle arrest; cell cycle S phase; cell proliferation; cell viability; controlled study; down regulation; drug cytotoxicity; drug efficacy; female; flow cytometry; G1 phase cell cycle checkpoint; human; human cell; immunohistochemistry; internal tandem duplication; leukemia cell; mouse; multiple cycle treatment; nonhuman; priority journal; protein cleavage; protein expression; protein phosphorylation; quantitative analysis; real time polymerase chain reaction; signal transduction; survival time; tandem repeat; tumor volume; upregulation; Western blotting; animal; antagonists and inhibitors; Bagg albino mouse; cell cycle checkpoint; dose response; drug effects; drug resistance; drug screening; enzymology; gene duplication; genetic predisposition; genetics; HL-60 cell line; K-562 cell line; Leukemia, Myeloid, Acute; metabolism; molecularly targeted therapy; nude mouse; pathology; phenotype; time factor; U-937 cell line; Anilides; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Cell Cycle Checkpoints; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; fms-Like Tyrosine Kinase 3; Gene Duplication; Genetic Predisposition to Disease; HL-60 Cells; Humans; K562 Cells; Leukemia, Myeloid, Acute; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Phenotype; Protein Kinase Inhibitors; Pyridines; Signal Transduction; Time Factors; Tumor Burden; U937 Cells; Xenograft Model Antitumor Assays
Publisher
Elsevier Ireland Ltd
Type
journal article