Sodium stibogluconate is a potent inhibitor of protein tyrosine phosphatases and augments cytokine responses in hemopoietic cell lines.
Using in vitro protein tyrosine phosphatase (PTPase) assays, we found that sodium stibogluconate, a drug used in treatment of leishmaniasis, is a potent inhibitor of PTPases Src homology PTPase1 (SHP-1), SHP-2, and PTP1B but not the dual-specificity phosphatase mitogen-activated protein kinase phosphatase 1. Sodium stibogluconate inhibited 99% of SHP-1 activity at 10 micrograms/ml, a therapeutic concentration of the drug for leishmaniasis. Similar degrees of inhibition of SHP-2 and PTP1B required 100 micrograms/ml sodium stibogluconate, demonstrating differential sensitivities of PTPases to the inhibitor. The drug appeared to target the SHP-1 domain because it showed similar in vitro inhibition of SHP-1 and a mutant protein containing the SHP-1 PTPase domain alone. Moreover, it forms a stable complex with the PTPase: in vitro inhibition of SHP-1 by the drug was not removed by a washing process effective in relieving the inhibition of SHP-1 by the reversible inhibitor suramin. The inhibition of cellular PTPases by the drug was suggested by its rapid induction of tyrosine phosphorylation of cellular proteins in Baf3 cells and its augmentation of IL-3-induced Janus family kinase 2/Stat5 tyrosine phosphorylation and proliferation of Baf3 cells. The augmentation of the opposite effects of GM-CSF and IFN-alpha on TF-1 cell growth by the drug indicated its broad activities in the signaling of various cytokines. These data represent the first evidence that sodium stibogluconate inhibits PTPases and augments cytokine responses. Our results provide novel insights into the pharmacological effects of the drug and suggest potential new therapeutic applications.
Pathak
M K
MK
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Yi
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D000818:Animals; D000966:Antimony Potassium Tartrate / Q000494:pharmacology; D000967:Antimony Sodium Gluconate / Q000493:pharmacokinetics / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D018797:Cell Cycle Proteins; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000032:analysis; D016898:Interferon-alpha / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D051379:Mice; D008894:Milk Proteins; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation / Q000187:drug effects; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D054645:Protein Phosphatase 1; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013498:Suramin / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism
D000981:Antiprotozoal Agents; D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D016898:Interferon-alpha; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D011355:Prodrugs; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D013498:Suramin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000966:Antimony Potassium Tartrate; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D000967:Antimony Sodium Gluconate