Effects of sodium stibogluconate on differentiation and proliferation of human myeloid leukemia cell lines in vitro.
PTPases are key signaling molecules and targets for developing novel therapeutics. We have studied the in vitro biological activity of PTPase inhibitor sodium stibogluconate (SS) on differentiation and proliferation of myeloid leukemia cell lines (NB4, HL-60 and U937). SS (250 microg/ml, 6 days) induced 87% of NB4 cells to reduce nitroblue tetrazolium (NBT), in comparison to the 90% induced by ATRA (1 microM, 6 days). SS treatment of NB4 cells resulted in an increase of CD11b expression and of a morphologically more mature population, coincident with growth arrest at S phase and increased cell death. The effect of SS on NB4 differentiation was irreversible and required continuous drug exposure. SS (400 microg/ml, 6 days) induced 60% and 55% of NBT-positive cells in HL-60 and U937 cell lines, which were augmented in the presence of GM-CSF (25 ng/ml) to levels (85% and 81%, respectively) comparable to those induced by ATRA. SS induced increased tyrosine phosphorylation of cellular proteins in the AML cell lines and inactivated SHP-1 PTPase in NB4 cells, consistent with SS functioning as a PTPase inhibitor in the leukemia cells. These results provide the first evidence of an anti-leukemia activity of SS as a PTPase inhibitor.
Pathak
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Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, OH 44195, USA.
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D000208:Acute Disease; D000967:Antimony Sodium Gluconate / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology*; D009580:Nitroblue Tetrazolium; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000276:immunology / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents; D047908:Intracellular Signaling Peptides and Proteins; D009580:Nitroblue Tetrazolium; D014443:Tyrosine; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D000967:Antimony Sodium Gluconate