4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione has been researched along with Leukemia--Myelogenous--Chronic--BCR-ABL-Positive* in 2 studies
2 other study(ies) available for 4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive
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Increased galectin-3 facilitates leukemia cell survival from apoptotic stimuli.
Galectin-3 is regulated for cancer cell survival and apoptosis depending upon the cell type and stimulus. We investigated a glycogen synthase kinase (GSK)-3β/galectin-3-regulated mechanism used by leukemia cells to escape from apoptotic stimuli. Galectin-3 expression was time- and transcription-dependently deregulated in K562 chronic myeloid leukemia cells stimulated for apoptosis by cisplatin (a platinum-based chemotherapy drug), sphingolipid ceramide analog C(2)-ceramide, and LY294002 (a phosphatidylinositol 3-kinase inhibitor). Notably, galectin-3 was upregulated in survival cells. Forced galectin-3 expression caused resistance to apoptosis, whereas knockdown galectin-3 expression increased susceptibility to apoptosis. Sub-cellular distribution of inducible galectin-3 was mitochondria-specific. Apoptotic stimuli decreased pro-survival Bcl-2 family protein expression (especially Mcl-1), whereas galectin-3 overexpression reversed but it was enhanced by a galectin-3 expression knockdown. Under apoptotic stimulation, GSK-3β was activated after Akt was inactivated and GSK-3β was inhibited-either pharmacologically or using short hairpin RNA to abolish galectin-3, increase apoptosis, and inhibit colony formation-which suggests a pro-survival role for GSK-3β. We found that GSK-3β upregulated galectin-3 and stabilized anti-apoptotic Bcl-2 family proteins, which is important for the escape of leukemia cells from apoptotic stimuli. Topics: Apoptosis; bcl-X Protein; Cell Line, Tumor; Cell Survival; Chromones; Drug Resistance, Neoplasm; Galectin 3; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mitochondria; Morpholines; Myeloid Cell Leukemia Sequence 1 Protein; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Thiadiazoles; Transcription, Genetic | 2011 |
Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8).
Leukemia is thought to arise from malignant stem cells, which have been described for acute and chronic myeloid leukemia (AML and CML) and for acute lymphoblastic leukemia (ALL). Leukemia stem cells (LSCs) are relatively resistant to current chemotherapy and likely contribute to disease relapse and progression. Consequently, the identification of drugs that can efficiently eradicate LSCs is an important priority. In the present study, we investigated the antileukemia activity of the compound TDZD-8. Analysis of primary AML, blast crisis CML (bcCML), ALL, and chronic lymphoblastic leukemia (CLL) specimens showed rapid induction of cell death upon treatment with TDZD-8. In addition, for myeloid leukemias, cytotoxicity was observed for phenotypically primitive cells, in vitro colony-forming progenitors, and LSCs as defined by xenotransplantation assays. In contrast, no significant toxicity was observed for normal hematopoietic stem and progenitor cells. Notably, cell death was frequently evident within 2 hours or less of TDZD-8 exposure. Cellular and molecular studies indicate that the mechanism by which TDZD-8 induces cell death involves rapid loss of membrane integrity, depletion of free thiols, and inhibition of both the PKC and FLT3 signaling pathways. We conclude that TDZD-8 uses a unique and previously unknown mechanism to rapidly target leukemia cells, including malignant stem and progenitor populations. Topics: Animals; Blast Crisis; Cell Death; Cell Membrane; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, SCID; Neoplastic Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase C; Signal Transduction; Sulfhydryl Compounds; Thiadiazoles; Tumor Cells, Cultured | 2007 |