Sodium Stibogluconate Is a Potent Inhibitor of Protein Tyrosine Phosphatases and Augments Cytokine Responses in Hemopoietic Cell Lines

Abstract

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 μg/ml, a therapeutic concentration of the drug for leishmaniasis. Similar degrees of inhibition of SHP-2 and PTP1B required 100 μg/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-α 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.

DCIR-mediated enhancement of HIV-1 infection requires the ITIM-associated signal transduction pathway

“…22 A treatment of Raji-CD4-DCIR cells with SSG for 10 minutes before pulsing with NL4-3 leads to a decrease in HIV-1 binding/entry, whereas it has no similar effect in parental Raji-CD4 cells ( Figure 2A). To determine more specifically which PTPase(s) is implicated in the signal transduced by DCIR after HIV-1 binding, we used specific antisense oligonucleotides directed against SHP-1 and SHP-2 DNA.…”

Inhibition of Src homology 2 domain‐containing phosphatase 1 increases insulin sensitivity in high‐fat diet‐induced insulin‐resistant mice

“…Pharmadynamic studies with sodium stibogluconate earlier revealed drug efficacy in the liver 30. The inhibitory effect with recombinant SHP‐1 has been shown earlier 22. Furthermore, both pharmacological approaches did not influence the expression of the PTPs SHP‐1, SHP‐2, PTP1B, TC‐PTP, DEP‐1 and LAR, which all have been implicated as regulators in insulin signalling or insulin resistance earlier.…”

“…In these experiments we could detect a small reduction (~ 13%, P = 0.065) in SHP‐1 activity (not shown). This suggests that – contrasting the strong in vivo metabolic effects and impact on recombinant SHP‐1 22 – the lack of a significant detectable SHP‐1 inhibition in tissues and cultured cells is presumably based on either transient inhibitory efficiency of sodium stibogluconate in vivo or on processing specifics of the animal tissues in vitro . Furthermore, our data showing in vivo efficacy are underlined by demonstration of sodium stibogluconate clearly reducing leishmanial skin lesions in a clinical study in patients applying also the same drug concentration (20 mg·kg −1 ·day −1 ) as in our experimental protocol 41.…”

Antigen-Dependent Integration of Opposing Proximal TCR-Signaling Cascades Determines the Functional Fate of T Lymphocytes

“…The T cell clone JKF6, specific for the melanoma differentiation Ag MART-1 [27][28][29][30][31][32][33][34][35] , was derived from tumor-infiltrating lymphocytes, as previously described (14). These T cells were expanded and activated by using 30 ng/ ml mAb OKT-3, irradiated PBMCs from three donors, and 500 IU/ml recombinant human IL-2.…”

“…1). Briefly, a specific TCR-like clonotypic mAb that recognizes the MART-1 [27][28][29][30][31][32][33][34][35] peptide, only when in complex with the HLA-A2 molecule, was used (16,17). JY cells were pulsed with different peptide concentrations, ranging from 500 mM down to 100 pM.…”