Anticancer activity of sodium stibogluconate in synergy with IFNs.
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.
Yi
Taolin
T
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, NB4-67, Cleveland, OH 44195, USA. yit@ccf.org
Pathak
Manas K
MK
Lindner
Daniel J
DJ
Ketterer
Michael E
ME
Farver
Carol
C
Borden
Ernest C
EC
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000967:Antimony Sodium Gluconate / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006131:Growth Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D016899:Interferon-beta / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D016899:Interferon-beta; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; D000967:Antimony Sodium Gluconate