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Background: B-cell lymphoma 2 (Bcl-2) family proteins are key regulators of apoptosis, which possess four conserved Bcl-2 homologies (BH) domains. Among the BH domains, the BH3 domain is considered as a potent 'death domain' while the BH4 domain is required for anti-apoptotic activity. Bcl-2 can be converted to a pro-apoptotic molecule through the removal or mutation of the BH4 domain. Bcl-2 is considered as an inducer of angiogenesis, which can promote tumor vascular network formation and further afford nutrients and oxygen to promote tumor progression. However, whether disrupting the function of the BH4 domain to convert Bcl-2 into a pro-apoptotic molecule could make Bcl-2 possess the potential for anti-angiogenic therapy remains to be defined. Methods: CYD0281 was designed and synthesized according to the lead structure of BDA-366, and its function on inducing a conformational change of Bcl-2 was further evaluated via immunoprecipitation (IP) and immunofluorescence (IF) assays. Moreover, the function of CYD0281 on apoptosis of endothelial cells was analyzed via cell viability, flow cytometry, and western blotting assays. Additionally, the role of CYD0281 on angiogenesis in vitro was determined via endothelial cell migration and tube formation assays and rat aortic ring assay. Chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, breast cancer cell xenograft tumor on CAM and in mouse models as well as the Matrigel plug angiogenesis assay were used to explore the effects of CYD0281 on angiogenesis in vivo. Results: We identified a novel potent small-molecule Bcl-2-BH4 domain antagonist, CYD0281, which exhibited significant anti-angiogenic effects both in vitro and in vivo, and further inhibited breast cancer tumor growth. CYD0281 was found to induce conformational changes in Bcl-2 through the exposure of the BH3 domain and convert Bcl-2 from an anti-apoptotic molecule into a cell death inducer, thereby resulting in the apoptosis of vascular endothelial cells. Conclusions: This study has revealed CYD0281 as a novel Bcl-2-BH4 antagonist that induces conformational changes of Bcl-2 to convert to a pro-apoptotic molecule. Our findings indicate that CYD0281 plays a crucial role in anti-angiogenesis and may be further developed as a potential anti-tumor drug candidate for breast cancer. This work also provides a potential anti-angiogenic strategy for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a common malignant tumor worldwide and poses a serious threat to human health. As a traditional Chinese medicine, Huaier (Trametes robiniophila Murr.) has been used in the clinical treatment of GC. However, the mechanism underlying the anticancer effect of Huaier remains poorly understood. In this study, we used in vivo imaging technology to determine the anticancer effect of the Huaier n-butanol extract (HBE) on orthotopic and hepatic metastasis of GC mouse models. We found that HBE suppressed tumor growth and metastasis without causing apparent host toxicity. Proteomic analysis of GC cells before and after HBE intervention revealed syntenin to be one of the most significantly downregulated proteins after HBE intervention. We further demonstrated that HBE suppressed the growth and metastasis of GC by reducing the expression of syntenin and the phosphorylation of STAT3 at Y705 and reversing the epithelial-mesenchymal transition (EMT). In addition, we confirmed that syntenin was highly expressed in GC tissue and correlated with metastasis and poor prognosis. In conclusion, our results suggest that Huaier, a clinically used anticancer drug, may inhibit the growth and liver metastasis of GC by inhibiting the syntenin/STAT3 signaling pathway and reversing EMT. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Decylubiquinone (DUb), a coenzyme Q10 analog, was reported to inhibit breast cancer growth and metastasis by us. However, the influence of DUb on CRC remains unclear. Herein, we found that DUb significantly inhibited CRC growth in the patient-derived xenograft (PDX) and CT26 xenograft models. DUb was further identified to significantly suppress CRC cell proliferation, colony formation, migration and invasion in a dose-dependent manner, while not inhibiting CRC cell apoptosis from flow cytometry assay. Sirtuin2 (SIRT2), a member of the sirtuin protein family, plays a critical role in growth and metastasis in various cancers. Moreover, DUb inhibited CRC progression by upregulating SIRT2. These findings reveal that DUb has the potential to a novel drug for the treatment of CRC by inhibiting CRC cell proliferation. [ABSTRACT FROM AUTHOR]

Abstract: Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide, and novel therapeutic strategies are urgently required to improve clinical outcome. Interferon-alpha (IFN-α) and sorafenib are widely used as anti-tumor agents against various malignancies. In this study, we investigated the combined effects of IFN-α and sorafenib against HCC. We demonstrated that the combination therapy synergistically suppressed HCC cellular viability, arrested cell cycle propagation and induced apoptosis in HCC cells. Further research revealed that IFN-α and sorafenib collaboratively regulated the expression levels of cell cycle-related proteins Cyclin A and Cyclin B as well as the pro-survival Bcl-2 family proteins Mcl-1, Bcl-2 and Bcl-XL. Moreover, sorafenib inhibited IFN-α induced oncogenic signaling of STAT3, AKT and ERK but not the activation of the tumor suppressor STAT1. Xenograft experiments also confirmed the combined effects of IFN-α and sorafenib on tumor growth inhibition and apoptosis induction in vivo. In conclusion, these results provide rationale for the clinical application of IFN-α and sorafenib combination therapy in HCC treatment. [Copyright &y& Elsevier]

CD8 + effector cells are highly skilled in immune surveillance and contribute to adaptive immunity against cancer cells. An increasing number of molecular factors affecting T-cell differentiation may alter T-cell function by increasing or decreasing the capacity of the immune system to kill cancer cells. Here, Sh3kbp1 binding protein 1 (Shkbp1), known as CIN85 binding protein or SETA binding protein, was found to be expressed in immune organs and immune cells. Shkbp1 knockout mice presented abnormal red and white pulp structures in spleen. Shkbp1 knockout increased CD8 + T cell number in spleen and enhanced the function of isolated CD8 + T cells from Shkbp1 knockout mice. The subcutaneous melanoma model in Shkbp1 knockout mice showed that tumor growth was inhibited, and the infiltration of CD8 + T cells in tumor tissue was increased. Furthermore, adenoviral therapy targeting Shkbp1 indicated that knockout of Shkbp1 increased CD8 + T cells and inhibited tumor growth. This study provides new insights into the role of Shkbp1 in CD8 differentiation and functions, suggesting that Shkbp1 may be a new, potential target in cancer immunotherapy. • Inflammatory molecules, Shkbp1, is high expression in various tumor type than its normal tissue, and immune cells express Shkbp1. • Knockout Shkbp1 increase CD8 +T cells number and function secreting more GZMB, PNF, IFN-γand TNF-α. • Tumor growths was suppressed in Shkbp1 KO mice, and adenoviral therapy targeting Shkbp1 inhibits tumor growth. [ABSTRACT FROM AUTHOR]

Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive. We employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice. Inhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway. Our findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC. [Display omitted] • EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC. • EPAC1 inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC. • NY0123 possesses a better anti-angiogenic efficacy than ESI-09. • Targeting EPAC1 inhibit angiogenesis through regulating VEGF and non-VEGF angiogenic signaling network. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are found frequently in patients and mice bearing tumors, which derived from immature myeloid cells. In healthy individuals, immature myeloid cells formed in the bone marrow differentiating to dendritic cells, macrophages and neutrophils. However, it is unclear whether some gene deficiency will lead to MDSCs accumulation in mice without bearing tumor. Here, we observed that MDSCs accumulated in the bone marrow of matrix metalloproteinase 12 knockout mice (MMP12 −/− mice) compared with wild type mice (MMP12 +/+ mice). And the number of CD4 + cells dramatically decreased, regulatory T cells was up-regulation and MDSCs function were determined. The results suggested that immune surveillance have been impaired in MMP12 −/− transgenic mice. After intravenous administration of B16 murine melanoma cells, MMP12 −/− mice developed more metastatic pulmonary nodules than MMP12 +/+ mice. Meanwhile, more MDSCs appeared in the tumors of MMP12 −/− mice compared with those of MMP12 +/+ mice. Mechanistically, we performed a MDSC blocking assay, finding that blockade of MDSCs resulted in reducing growth of tumors in MMP12 −/− mice. Furthermore, we ascertained that macrophages in MMP12 −/− mice abundantly secrete IL-1β in bone marrow which induce the accumulation of MDSCs in the bone marrow. Together, these results demonstrated that the macrophages in MMP12 −/− mice could crosstalk with myeloid cells through IL-1β, inducing MDSCs accumulation, then contributing to tumor growth. It has revealed that the critical roles of macrophage in myeloid cells differentiation. [ABSTRACT FROM AUTHOR]