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Immune-Mediated Antitumor Effect By VEGFR2 Selective Inhibitor For Gastric Cancer.

ABSTRACT: Background:It was previously reported that targeting vascular epithelial growth factor (VEGF)/VEGFR could modulate the antitumor immunity. VEGFR2 inhibitor YN968D1 is a highly selective VEGFR2 inhibitor and was approved for the treatment of late-stage gastric cancer in 2014, but its role in antitumor immunity remains unknown. Materials and methods:In this study, we investigated the effects of YN968D1 on the function of T cells in vitro by testing the cytotoxicity and cytokine production. Next, we constructed peritoneal dissemination and subcutaneous gastric cancer mouse model to assess the cytotoxicity of YN968D1-treated T cells in vivo, respectively. Results:We found that the use of YN968D1 in CD8+ T cells could reduce the expression levels of inhibitory checkpoints, such as Lag-3, PD-1, and Tim3, escalate the production of IFN-? and IL-2 and promote the cytotoxicity of T cells dramatically in vitro. The transfer of YN968D1-treated T cells achieved better tumor control compared to DMSO-treated T cells or control in both peritoneal dissemination and subcutaneous gastric cancer mouse models. Conclusion:Our results indicate that YN968D1 can enhance the T cell-mediated antitumor immunity.

SUBMITTER: Yang J

PROVIDER: S-EPMC6863181 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Immune-Mediated Antitumor Effect By VEGFR2 Selective Inhibitor For Gastric Cancer.

Yang Ju J Yan Jing J Shao Jie J Xu Qiuping Q Meng Fanyan F Chen Fangjun F Ding Naiqing N Du Shiyao S Zhou Shujuan S Cai Juan J Wang Qin Q Liu Baorui B

OncoTargets and therapy 20191115

<h4>Background</h4>It was previously reported that targeting vascular epithelial growth factor (VEGF)/VEGFR could modulate the antitumor immunity. VEGFR2 inhibitor YN968D1 is a highly selective VEGFR2 inhibitor and was approved for the treatment of late-stage gastric cancer in 2014, but its role in antitumor immunity remains unknown.<h4>Materials and methods</h4>In this study, we investigated the effects of YN968D1 on the function of T cells in vitro by testing the cytotoxicity and cytokine prod ...[more]

PMID: 31814734

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Project description:BackgroundThe transcription factor nuclear factor-?B (NF-?B) is constitutively activated in a variety of human cancers, including gastric cancer. NF-?B inhibitors that selectively kill cancer cells are urgently needed for cancer treatment. Curcumin is a potent inhibitor of NF-?B activation. Unfortunately, the therapeutic potential of curcumin is limited by its relatively low potency and poor cellular bioavailability. In this study, we presented a novel NF-?B inhibitor named Da0324, a synthetic asymmetric mono-carbonyl analog of curcumin. The purpose of this study is to research the expression of NF-?B in gastric cancer and the antitumor activity and mechanism of Da0324 on human gastric cancer cells.MethodsThe expressions between gastric cancer tissues/cells and normal gastric tissues/cells of NF-?B were evaluated by Western blot. The inhibition viability of compounds on human gastric cancer cell lines SGC-7901, BGC-823, MGC-803, and normal gastric mucosa epithelial cell line GES-1 was assessed with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Absorption spectrum method and high-performance liquid chromatography method detected the stability of the compound in vitro. The compound-induced changes of inducible NF-?B activation in the SGC-7901 and BGC-823 cells were examined by Western blot analysis and immunofluorescence methods. The antitumor activity of compound was performed by clonogenic assay, matrigel invasion assay, flow cytometric analysis, Western blot analysis, and Hoechst 33258 staining assay.ResultsHigh levels of p65 were found in gastric cancer tissues and cells. Da0324 displayed higher growth inhibition against several types of gastric cancer cell lines and showed relatively low toxicity to GES-1. Moreover, Da0324 was more stable than curcumin in vitro. Western blot analysis and immunofluorescence methods showed that Da0324 blocked NF-?B activation. In addition, Da0324 significantly inhibited tumor proliferation and invasion, arrested the cell cycle, and induced apoptosis in vitro.ConclusionThe asymmetric mono-carbonyl analog of curcumin Da0324 exhibited significantly improved antigastric cancer activity. Da0324 may be a promising NF-?B inhibitor for the selective targeting of cancer cells. However, further studies are needed in animals to validate these findings for the therapeutic use of Da0324.

Project description:BackgroundOverexpression of Aurora A and B has been reported in a wide range of tumor types, including gastric cancer. Anti-angiogenesis has been considered as an important therapeutic modality in advanced gastric cancer. Here we identified a novel compound TY-011 with promising antitumor activity by targeting mitotic kinases (Aurora A and B) and angiogenic receptor tyrosine kinase (VEGFR2).MethodsHTRF® KinEASE™ assay was used to detect the effect of TY-011 against Aurora A, Aurora B and VEGFR2 activities. Docking simulation study was performed to predict the binding mode of TY-011 with Aurora A and B kinases. CCK-8 assay was used to test cell growth. Cell cycle and cell apoptosis was analyzed by flow cytometry. Gastric cancer cell xenograft mouse models were used for in vivo study. TUNEL kit was used to determine the apoptosis of tumor tissues. Immunohistochemistry analysis and HUVEC tube formation assay were performed to determine the anti-angiogenesis ability. Immunofluorescence and western blot were used to test protein expression.ResultsTY-011 was identified as a potential Aurora A and B inhibitor by HTRF® KinEASE™ assay. It effectively inhibited cellular Aurora A and B activities in a concentration-dependent manner. TY-011 occupied the ATP-binding site of both Aurora A and B kinases. TY-011 demonstrated prominent inhibitory effects on proliferation of gastric cancer cells. TY-011 treatment induced an obvious accumulation of cells at G2/M phase and a modest increase of cells with >4 N DNA content, which then underwent apoptosis. Meaningfully, orally administration of TY-011 demonstrated superior efficacy against the tumor growth in gastric cancer cell xenograft, with ~90% inhibition rate and 100% tumor regression at 9 mg/kg dose, and TY-011 did not affect the body weight of mice. Interestingly, we observed that TY-011 also antagonized tumor angiogenesis by targeting VEGFR2 kinase.ConclusionsThese results indicate that TY-011 is a well-tolerated, orally active compound that targets mitosis and angiogenesis in tumor growth, and provides strong preclinical support for use as a therapeutic for human gastric cancers.

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Immune-Mediated Antitumor Effect By VEGFR2 Selective Inhibitor For Gastric Cancer.

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Immune-Mediated Antitumor Effect By VEGFR2 Selective Inhibitor For Gastric Cancer.

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