Related Experiment Videos
Anticancer activity of sodium stibogluconate in synergy with IFNs
Taolin Yi1, Manas K Pathak, Daniel J Lindner
1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, NB4-67, Cleveland, OH 44195, USA. yit@ccf.org
Abstract:
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.
Insights
Sodium stibogluconate (SSG) combined with interferon-alpha (IFN-alpha) overcomes cancer cell resistance to IFN-alpha. This combination therapy eradicated tumors in mice, showing potential for treating refractory cancers.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Cancer cell resistance to interferon-alpha (IFN-alpha) limits its therapeutic efficacy.
- Developing strategies to overcome IFN-alpha resistance is crucial for effective cancer treatment.
Purpose of the Study:
- To investigate the synergistic effect of sodium stibogluconate (SSG) and IFN-alpha in overcoming IFN-alpha resistance in cancer.
- To elucidate the molecular mechanisms underlying the combined therapeutic effect of SSG and IFN-alpha.
Main Methods:
- Testing the combination of SSG and IFN-alpha on various human cancer cell lines in vitro.
- Evaluating the efficacy of SSG and IFN-alpha in eradicating IFN-alpha-refractory melanoma tumors in nude mice.
- Analyzing the impact of SSG on IFN-alpha signaling pathways, including Stat1 tyrosine phosphorylation and phosphatase activity (SHP-1, SHP-2).
Main Results:
- SSG and IFN-alpha demonstrated synergistic activity against multiple human cancer cell lines.
- The combination therapy eradicated IFN-alpha-refractory melanoma tumors in mice with no significant toxicity.
- SSG enhanced IFN-alpha-induced Stat1 phosphorylation and inactivated intracellular phosphatases SHP-1 and SHP-2.
- SSG treatment induced cellular protein tyrosine phosphorylation, indicating phosphatase inhibition.
Conclusions:
- SSG can overcome IFN-alpha resistance in cancer, offering a potential therapeutic strategy.
- The mechanism involves SSG's ability to inhibit protein tyrosine phosphatases, thereby enhancing IFN-alpha signaling.
- Selective compounds within SSG show promise as clinically usable protein tyrosine phosphatase inhibitors for cancer treatment.