Journal
JOURNAL OF IMMUNOLOGY
Volume 169, Issue 10, Pages 5978-5985Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.169.10.5978
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Funding
- NCI NIH HHS [CA 90914, R01 CA 79891] Funding Source: Medline
- PHS HHS [R01 MG 58893] Funding Source: Medline
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Cancer cell resistance limits the efficacy of IFNs. In this study, we show that sodium stibogluconate (SSG) and IFN-alpha synergized to overcome IFN-alpha resistance in various human cancer cell lines in culture and eradicated IFN-alpha-refractory WM9 human melanoma tumors in nude mice with no obvious toxicity. SSG enhanced IFN-alpha-induced Stat1 tyrosine phosphorylation, inactivated intracellular SHP-1 and SHP-2 that negatively regulate IFN signaling, and induced cellular protein tyrosine phosphorylation in cancer cell lines. These effects are consistent with inactivation of phosphatases as the basis of SSG anticancer activity. Characterization of SSG by chromatography revealed that only selective compounds in SSG were effective protein tyrosine phosphatase inhibitors. These observations suggest the potential of SSG as a clinically usable protein tyrosine phosphatase inhibitor in cancer treatment and provide insights for developing phosphatase-targeted therapeutics.
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