lithium-chloride and Leukemia--Myeloid--Acute

Tripartite motif (TRIM) 31 is a member of TRIM family and exerts oncogenic role in the progression and drug resistance of several cancers. However, little is known about the relevance of TRIM31 in acute myeloid leukemia (AML). Herein, we investigated the role of TRIM31 in AML. We examined the expression levels of TRIM31 in the blood samples from 34 patients with AML and 34 healthy volunteers using qRT-PCR. The mRNA levels of TRIM31 in human bone marrow stromal cells (HS-5) and five AML cell lines were also detected. Loss/gain-of-function assays were performed to assess the role of TRIM31 in AML cells proliferation, apoptosis and sensitivity to daunorubicin. The expression levels of pro-caspase 3, cleaved caspase 3, Wnt3a, β-catenin, cyclin D1 and c-Myc were measured using Western blot. TRIM31 expression levels were significantly up-regulated in AML patients and cell lines. Knockdown of TRIM31 suppressed cell proliferation and promoted apoptosis in AML-5 and U937 cells. The IC50 of daunorubicin was significantly decreased in TRIM31 siRNA (si-TRIM31) transfected cells. Oppositely, induced cell proliferation and decreased cell apoptosis were observed in pcDNA-3.1-TRIM31 transfected cells. Furthermore, knockdown of TRIM31 suppressed the activation of Wnt/β-catenin pathway in AML cells. Activation of Wnt/β-catenin pathway by LiCl abolished the effects of si-TRIM31 on cell proliferation, apoptosis and sensitivity to daunorubicin in AML cells. In conclusion, the results indicated that TRIM31 promoted leukemogenesis and chemoresistance to daunorubicin in AML. The oncogenic role of TRIM31 in AML was mediated by the Wnt/β-catenin pathway. Thus, TRIM31 might serve as a therapeutic target for the AML treatment.

Topics: Antibiotics, Antineoplastic; Apoptosis; Case-Control Studies; Cell Line, Tumor; Cell Proliferation; Daunorubicin; Disease Progression; Drug Resistance, Neoplasm; Healthy Volunteers; Humans; Leukemia, Myeloid, Acute; Lithium Chloride; RNA, Small Interfering; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Wnt Signaling Pathway

GSK3α has been identified as a new target in the treatment of acute myeloid leukemia (AML). However, most GSK3 inhibitors lack specificity for GSK3α over GSK3β and other kinases. We have previously shown in lung cancer cells that GSK3α and to a lesser extent GSK3β are inhibited by the advanced clinical candidate tivantinib (ARQ197), which was designed as a MET inhibitor. Thus, we hypothesized that tivantinib would be an effective therapy for the treatment of AML. Here, we show that tivantinib has potent anticancer activity across several AML cell lines and primary patient cells. Tivantinib strongly induced apoptosis, differentiation and G2/M cell cycle arrest and caused less undesirable stabilization of β-catenin compared to the pan-GSK3 inhibitor LiCl. Subsequent drug combination studies identified the BCL-2 inhibitor ABT-199 to synergize with tivantinib while cytarabine combination with tivantinib was antagonistic. Interestingly, the addition of ABT-199 to tivantinib completely abrogated tivantinib induced β-catenin stabilization. Tivantinib alone, or in combination with ABT-199, downregulated anti-apoptotic MCL-1 and BCL-XL levels, which likely contribute to the observed synergy. Importantly, tivantinib as single agent or in combination with ABT-199 significantly inhibited the colony forming capacity of primary patient AML bone marrow mononuclear cells. In summary, tivantinib is a novel GSK3α/β inhibitor that potently kills AML cells and tivantinib single agent or combination therapy with ABT-199 may represent attractive new therapeutic opportunities for AML.

Topics: Apoptosis; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Down-Regulation; Drug Repositioning; Drug Synergism; G2 Phase Cell Cycle Checkpoints; Glycogen Synthase Kinase 3; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Lithium Chloride; Myeloid Cell Leukemia Sequence 1 Protein; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrrolidinones; Quinolines; Sulfonamides

The influence of lithium chloride on the proliferation of normal granulocyte-macrophage progenitor cells (CFU-GM) and clonogenic blasts (CFU-L) from patients with acute myeloid leukaemia in the semisolid cultures in vitro was investigated. It was observed that while lithium chloride with the concentration of 2 mmol/l increases the number of CFU-GM colonies, it does not increase the number of CFU-L colonies and clusters. Our studies indicate that lithium salts can be used for the treatment of patients with acute myeloid leukaemia after intensive chemotherapy.

Topics: Cell Division; Cells, Cultured; Chlorides; Colony-Forming Units Assay; Granulocytes; Hematopoiesis; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Lithium; Lithium Chloride; Macrophages; Neoplastic Stem Cells

Lithium is known to cause leucocytosis in normal humans, and lithium salts have been used therapeutically in attenuating leucopenia in patients undergoing chemotherapy. Recent reports also described leukaemia development during lithium treatment. We have investigated the effect of lithium chloride on the proliferation of human myeloid, erythroblastic, and T- and B-lymphoblast leukaemia cells in vitro. Colony formation by cells of the myeloid leukaemia lines HL-60 and KG-1 was enhanced by lithium chloride, and maximal stimulation was seen at 5 X 10(-4) M. Lithium also increased the proliferation of KG-1a cells, a subline of KG-1 cells that does not respond to colony-stimulating factor, indicating a direct growth-promoting effect on myeloid leukaemia cells. Lithium was found to enhance colony formation by the T-lymphoblast cell line MOLT 4 and the B-lymphoblast line IM-9 at concentrations between 10(-6) and 10(-3) M. The addition of lithium chloride to murine Friend or human K-562 erythroleukaemia cells also caused an augmentation in colony formation. These observations may have relevance to the therapeutic use of lithium in patients with haematological malignancies.

Topics: Animals; Cell Division; Cell Line; Chlorides; Dose-Response Relationship, Drug; Hematopoietic Stem Cells; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Experimental; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lithium; Lithium Chloride; Mice