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Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
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-
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.
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