Interferon-γ Is Induced in Human Peripheral Blood Immune Cells<i>In Vitro</i>by Sodium Stibogluconate/Interleukin-2 and Mediates Its Antitumor Activity<i>In Vivo</i>

Fan, Keke; Borden, Ernest C.; Yi, Taolin

doi:10.1089/jir.2008.0061

Cited by 11 publications

(11 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, SSG due to its ability to inhibit SHP-1 has been shown to enhance Tcon effector function (24, 38). When we tested the effect of SSG under suboptimal peptide concentrations where SSG augments Tcon cell proliferation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, CD103+ Treg cells, which we found to be enriched in SHP-1-deficient mice, have been shown to be the subpopulation accumulating at the site of Leishmania infection (44). In addition, more recent studies have proposed an anti-tumor effect for SSG via a T cell dependent mechanism (24, 25). In fact, SSG is currently tested in several phase 1 clinical trials for patients with advanced solid tumors, lymphoma, or myeloma (27-29).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Protein Tyrosine Phosphatase SHP-1 Modulates the Suppressive Activity of Regulatory T Cells

Iype

Sankarshanan

Mauldin

et al. 2010

The Journal of Immunology

View full text Add to dashboard Cite

The importance of regulatory T cells (Tregs) for immune tolerance is well recognized, yet the signaling molecules influencing their suppressive activity are relatively poorly understood. In this article, through in vivo studies and complementary ex vivo studies, we make several important observations. First, we identify the cytoplasmic tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1) as an endogenous brake and modifier of the suppressive ability of Tregs; consistent with this notion, loss of SHP-1 expression strongly augments the ability of Tregs to suppress inflammation in a mouse model. Second, specific pharmacological inhibition of SHP-1 enzymatic activity via the cancer drug sodium stibogluconate potently augmented Treg suppressor activity both in vivo and ex vivo. Finally, through a quantitative imaging approach, we directly demonstrate that Tregs prevent the activation of conventional T cells and that SHP-1–deficient Tregs are more efficient suppressors. Collectively, our data reveal SHP-1 as a critical modifier of Treg function and a potential therapeutic target for augmenting Treg-mediated suppression in certain disease states.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Protein Tyrosine Phosphatase SHP-1 Modulates the Suppressive Activity of Regulatory T Cells

Iype

Sankarshanan

Mauldin

et al. 2010

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…IFNγ+ cells were induced by SSG in its anti-Renca tumor action (34) and in human peripheral blood samples in vitro (35). As a further step to assess TPI-1, the capacity of the SHP-1 inhibitor to induce primary IFNγ + cells in mouse splenocytes and human peripheral blood in vitro were evaluated in comparison with SSG.…”

Section: Resultsmentioning

confidence: 99%

“…SSG selectively inhibited the PTP SHP-1 (29), which negatively controls the activation of immune cells (14, 21, 30) essential for anti-tumor immunity (1) and down regulates the signaling of anti-tumor cytokines (31–33). Consistent with targeting SHP-1, SSG had anti-renal tumor activity mediated via activating TH1 cells (IFNγ + T cells) in mice when combined with IL-2 (34) and required IFNγ for anti-tumor action (35). SSG also synergized with IFNα in mouse models to eradicate melanoma tumors (36) and to inhibit the growth of prostate cancer tumors (37).…”

Section: Introductionmentioning

confidence: 86%

Novel SHP-1 Inhibitors Tyrosine Phosphatase Inhibitor-1 and Analogs with Preclinical Anti-Tumor Activities as Tolerated Oral Agents

Kundu¹,

Fan²,

Cao³

et al. 2010

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Src homology region 2 domain-containing phosphatase 1 (SHP-1) has been implicated as a potential cancer therapeutic target by its negative regulation of immune cell activation and the activity of the SHP-1 inhibitor sodium stibogluconate that induced IFN-γ+ cells for anti-tumor action. To develop more potent SHP-1-targeted anti-cancer agents, inhibitory leads were identified from a library of 34,000 drug-like compounds. Among the leads and active at low nM for recombinant SHP-1, tyrosine phosphatase inhibitor-1 (TPI-1) selectively increased SHP-1 phospho-substrates (pLck-pY394, pZap70, and pSlp76) in Jurkat T cells but had little effects on pERK1/2 or pLck-pY505 regulated by phosphatases SHP-2 or CD45, respectively. TPI-1 induced mouse splenic–IFN-γ+ cells in vitro, ∼58-fold more effective than sodium stibogluconate, and increased mouse splenic-pLck-pY394 and –IFN-γ+ cells in vivo. TPI-1 also induced IFN-γ+ cells in human peripheral blood in vitro. Significantly, TPI-1 inhibited (∼83%, p < 0.002) the growth of B16 melanoma tumors in mice at a tolerated oral dose in a T cell-dependent manner but had little effects on B16 cell growth in culture. TPI-1 also inhibited B16 tumor growth and prolonged tumor mice survival as a tolerated s.c. agent. TPI-1 analogs were identified with improved activities in IFN-γ+ cell induction and in anti-tumor actions. In particular, analog TPI-1a4 as a tolerated oral agent completely inhibited the growth of K1735 melanoma tumors and was more effective than the parental lead against MC-26 colon cancer tumors in mice. These results designate TPI-1 and the analogs as novel SHP-1 inhibitors with anti-tumor activity likely via an immune mechanism, supporting SHP-1 as a novel target for cancer treatment.

show abstract

“…Following staining, the samples were washed 3 times, re-suspended in 200 μl of 1% para-formaldehyde solution and analyzed (20,000 cells/sample) using a BD FACS Caliburs cytometer as described previously (32, 33). …”

Section: Methodsmentioning

confidence: 99%

Tyrosine Phosphatase Inhibitor-3 Sensitizes Melanoma and Colon Cancer to Biotherapeutics and Chemotherapeutics

Kundu

Fan

Cao

et al. 2010

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Drug resistance is a major obstacle in cancer treatments and diminishes the clinical efficacy of biological, cytotoxic, or targeted therapeutics. Being an antiapoptotic mediator of chemoresistance in breast and lung cancer cells, MKP1 phosphatase might be targeted for overcoming chemoresistance and improving therapeutic efficacy. In this work, tyrosine phosphatase inhibitor-3 (TPI-3) was identified as a novel small molecule inhibitor of MKP1 and was capable of sensitizing tumors to bio-and chemotherapeutics in mice as a tolerated oral agent. Effective against recombinant MKP1, TPI-3 selectively increased MKP1 phosphosubstrates in Jurkat cells and induced cell death via apoptosis at nanomolar concentrations. TPI-3 also increased MKP1 phosphosubstrates in WM9 human melanoma cells and synergized with biotherapeutic IFNα2b in the growth inhibition of melanoma cells in vitro (combination index, <1). WM9 xenografts unresponsive to individual agents were significantly inhibited (62%, P = 0.001) in mice by a tolerated combination of oral TPI-3 (10 mg/kg, 5 d/wk) and IFNα2b. MKP1 expression was detected in human melanoma cell lines and tissue samples at levels up to six times higher than those in normal or nonmalignant melanocytes. TPI-3 also interacted positively with chemotherapeutics, 5-fluorouracil/leucovorin, against MC-26 colon cancer cells in vitro and in mice. Altogether, our data show the preclinical activities of TPI-3 in overcoming cancer resistance to bio-and chemotherapeutics, implicate MKP1 as a drug-resistant molecule in melanoma, and support the targeting of MKP1 for improving cancer therapeutic efficacy. Mol Cancer Ther; 9(8);

show abstract

Interferon-γ Is Induced in Human Peripheral Blood Immune CellsIn Vitroby Sodium Stibogluconate/Interleukin-2 and Mediates Its Antitumor ActivityIn Vivo

Cited by 11 publications

References 36 publications

The Protein Tyrosine Phosphatase SHP-1 Modulates the Suppressive Activity of Regulatory T Cells

The Protein Tyrosine Phosphatase SHP-1 Modulates the Suppressive Activity of Regulatory T Cells

Novel SHP-1 Inhibitors Tyrosine Phosphatase Inhibitor-1 and Analogs with Preclinical Anti-Tumor Activities as Tolerated Oral Agents

Tyrosine Phosphatase Inhibitor-3 Sensitizes Melanoma and Colon Cancer to Biotherapeutics and Chemotherapeutics

Contact Info

Product

Resources

About