Anticancer Activity of Sodium Stibogluconate in Synergy with IFNs

Yi, Taolin; Pathak, Manoj Kumar; Lindner, Daniel J.; Ketterer, Michael E.; Farver, Carol; Borden, Ernest C.

doi:10.4049/jimmunol.169.10.5978

Cited by 67 publications

(74 citation statements)

References 33 publications

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“…Consistent with inhibition of a negative signaling regulator, SSG augmented signaling and cell responses to IL-3, erythropoietin, and IFNs in vitro (9). This action mechanism of SSG in vivo was indicated by its interaction with IFN-␣ in a synergistic manner to eradicate WM9 melanoma tumors in nude mice (10). Inhibition of a negative regulatory PTPase of intracellular signaling may also play a role in the drug's anti-Leishmania action.…”

Section: R Enal Cell Carcinoma (Rcc)mentioning

confidence: 76%

“…Sodium stibogluconate (SSG) was identified recently as a clinically usable PTPase inhibitor that has antimelanoma potential in combination with IFNs (9,10). SSG is an anti-Leishmania drug with a previously undefined mechanism of action (11).…”

Section: R Enal Cell Carcinoma (Rcc)mentioning

confidence: 99%

“…Recombinant IL-2 (Proleukin; 22 million IU/1.3 mg; Chiron) was purchased from the Cleveland Clinic Foundation pharmacy. SSG has been described previously (10). For cell growth inhibition assays, cells were cultured in the absence or the presence of various amounts of SSG for 6 days, with viable cells quantified by MTT assays as described previously (9).…”

Section: Reagents Cells Cell Culture and Cell Growth Inhibition Asmentioning

confidence: 99%

“…H&E-stained tissue sections of the fixed samples were prepared and evaluated by microscopy as described previously (10). Preparation of frozen tissue sections and immunohistochemistry were performed following established procedures (26).…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

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Sodium Stibogluconate Interacts with IL-2 in Anti-Renca Tumor Action via a T Cell-Dependent Mechanism in Connection with Induction of Tumor-Infiltrating Macrophages

Fan¹,

Zhou²,

Pathak³

et al. 2005

The Journal of Immunology

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IL-2 therapy results in 10–20% response rates in advanced renal cell carcinoma (RCC) via activating immune cells, in which the protein tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 (SHP-1) is a key negative regulator. Based on finding that sodium stibogluconate (SSG) inhibited SHP-1, the anti-RCC potential and action mechanism of SSG and SSG/IL-2 in combination were investigated in a murine renal cancer model (Renca). Despite its failure to inhibit Renca cell proliferation in cultures, SSG induced 61% growth inhibition of Renca tumors in BALB/c mice coincident with an increase (2-fold) in tumor-infiltrating macrophages (Mφ). A combination of SSG and IL-2 was more effective in inhibiting tumor growth (91%) and inducing tumor-infiltrating Mφ (4-fold), whereas IL-2 alone had little effect. Mφ increases were also detected in the spleens of mice treated with SSG (3-fold) or SSG/IL-2 in combination (6-fold), suggesting a systemic Mφ expansion similar to those in SHP-deficient mice. T cell involvement in the anti-Renca tumor action of the combination was suggested by the observations that the treatment induced spleen IFN-γ T cells in BALB/c mice, but failed to inhibit Renca tumor growth in athymic nude mice and that SSG treatment of T cells in vitro increased production of IFN-γ capable of activating tumoricidal Mφ. The SSG and SSG/IL-2 combination treatments were tolerated in the mice. These results together demonstrate an anti-Renca tumor activity of SSG that was enhanced in combination with IL-2 and functions via a T cell-dependent mechanism with increased IFN-γ production and expansion/activation of Mφ. Our findings suggest that SSG might improve anti-RCC efficacy of IL-2 therapy by enhancing antitumor immunity.

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Section: R Enal Cell Carcinoma (Rcc)mentioning

confidence: 76%

Section: R Enal Cell Carcinoma (Rcc)mentioning

confidence: 99%

Section: Reagents Cells Cell Culture and Cell Growth Inhibition Asmentioning

confidence: 99%

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

See 2 more Smart Citations

Sodium Stibogluconate Interacts with IL-2 in Anti-Renca Tumor Action via a T Cell-Dependent Mechanism in Connection with Induction of Tumor-Infiltrating Macrophages

Fan¹,

Zhou²,

Pathak³

et al. 2005

The Journal of Immunology

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“…Receptor signaling is suppressed by the phosphatases SHP-1 and SHP-2 and by the induced SOCS and PIAS proteins [1,14,25]. The phosphorylated ISGF-3 complex is translocated to the nucleus and forms (with the addition of a third subunit, p48 or IRF-9), a DNA binding complex specific for the IFNstimulated response element.…”

Section: Interferons and Stimulated Genes In Melanomamentioning

confidence: 99%

Augmentation of effects of interferon-stimulated genes by reversal of epigenetic silencing: Potential application to melanoma

Borden¹

2007

Cytokine & Growth Factor Reviews

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Increased expression of genes, silenced by methylation of their promoters, could have relevance for increasing effects of not only interferons (IFNs) but also APO2L/TRAIL, cytotoxics and immunotherapeutics for melanoma and other malignancies. A resistant melanoma cell line, A375, lacked APO2L/TRAIL or apoptosis induction by either IFN-α2 or IFN-β. However, apoptosis was induced by IFNs in A375 cells by 5-aza, 2′deoxycytidine, evaluated based upon the postulate that promoter methylation might be silencing pro-apopoptotic IFN-stimulated genes (ISGs). RASSF1A, commonly methylated at high frequency in many tumors including melanoma, which we discovered to be also an IFN-regulated gene, was increased by 5-Aza-dC. RASSF1A was important in enhancing apoptotic effects of not only IFNs and APO2L/TRAIL but also cisplatin. Unraveling epigenetic regulatory mechanisms, as yet only partially identified, will result in new biological insights and improved strategies for therapeutic use of IFNs or ISGs such as APO2L/TRAIL.

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Cross the Undruggable Barrier, the Development of SHP2 Inhibitors: From Catalytic Site Inhibitors to Allosteric Inhibitors

Guo

Dong

et al. 2021

ChemistrySelect

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SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is a unique protein tyrosine phosphatase(PTP)encoded by the PTPN11 gene, which is composed of two SH2 domains (N-SH2, C-SH2) and the PTP domain. SHP2 is essential in several oncogenic signaling pathways (especially Ras/Raf/ MAPK) and has a wide range of mutations in various cancers. Therefore, the development of inhibitors of SHP2 has become the focus of anticancer research in recent years. Initially, the researchers hoped to directly inhibit SHP2 activity by targeting its catalytic sites like other PTP inhibitors' development.However, the high homology and strong positivity of PTP catalytic sites bring great difficulties in developing such inhibitors. Finally, in 2015, a compact molecule (SHP099) passed the undruggable barrier of SHP2 through the allosteric tunnel. In this paper, the development of SHP2 inhibitors in recent years will be reviewed to transition from catalytic site inhibitors to allosteric inhibitors to provide suggestions for the development and application of SHP2 inhibitors and other PTP inhibitors.

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Anticancer Activity of Sodium Stibogluconate in Synergy with IFNs

Cited by 67 publications

References 33 publications

Sodium Stibogluconate Interacts with IL-2 in Anti-Renca Tumor Action via a T Cell-Dependent Mechanism in Connection with Induction of Tumor-Infiltrating Macrophages

Sodium Stibogluconate Interacts with IL-2 in Anti-Renca Tumor Action via a T Cell-Dependent Mechanism in Connection with Induction of Tumor-Infiltrating Macrophages

Augmentation of effects of interferon-stimulated genes by reversal of epigenetic silencing: Potential application to melanoma

Cross the Undruggable Barrier, the Development of SHP2 Inhibitors: From Catalytic Site Inhibitors to Allosteric Inhibitors

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