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      Identification of viral SIM-SUMO2-interaction inhibitors for treating primary effusion lymphoma

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          Abstract

          Primary effusion lymphoma (PEL) is an aggressive B-cell malignancy without effective treatment, and caused by the infection of Kaposi’s sarcoma-associated herpesvirus (KSHV), predominantly in its latent form. Previously we showed that the SUMO2-interacting motif within the viral latency-associated nuclear antigen (LANA SIM) is essential for establishment and maintenance of KSHV latency. Here, we developed a luciferase based live-cell reporter system to screen inhibitors selectively targeting the interaction between LANA SIM and SUMO2. Cambogin, a bioactive natural product isolated from the Garcinia genus (a traditional herbal medicine used for cancer treatment), was obtained from the reporter system screening to efficiently inhibit the association of SUMO2 with LANA SIM, in turn reducing the viral episome DNA copy number for establishment and maintenance of KSHV latent infection at a low concentration (nM). Importantly, Cambogin treatments not only specifically inhibited proliferation of KSHV-latently infected cells in vitro, but also induced regression of PEL tumors in a xenograft mouse model. This study has identified Cambogin as a novel therapeutic agent for treating PEL as well as eliminating persistent infection of oncogenic herpesvirus.

          Author summary

          Primary effusion lymphoma is a common AIDS-associated malignancy caused by infection with Kaposi’s sarcoma-associated herpesvirus (KSHV), and is currently absence of efficient and specific treatment. Natural product from herbal medicines is a major source of drug discovery for the treatment of a variety of diseases. In this study, the authors demonstrated that Cambogin, a polycyclic polyprenylated acylphloroglucinols (PPAPs) isolated from the branches of Garcinia esculenta (a tropical evergreen tree and traditional cancer treatment across Southern Asia), is a potent and effective inhibitor of KSHV-latently infected cells at a low concentration (nM) in vitro and in vivo, through targeting viral LANA SIM-SUMO2 interaction.

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          Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth.

          Neovascularization is critical for the growth of tumours and is a dominant feature in a variety of angiogenic diseases such as diabetic retinopathy, haemangiomas, arthritis and psoriasis. Recognition of the potential therapeutic benefit of controlling unabated capillary growth has led to a search for safe and effective angiogenesis inhibitors. We report here the synthesis of a family of novel inhibitors that are analogues of fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius. We first isolated this fungus from a contaminated culture of capillary endothelial cells. Purified fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice, but prolonged administration was limited because it caused severe weight loss. Synthesis of fumagillin analogues yielded potent angiogenesis inhibitors ('angioinhibins') which suppress the growth of a wide variety of tumours with relatively few side-effects.
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            Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma.

            The biology of Kaposi sarcoma is poorly understood because the dominant cell type in Kaposi sarcoma lesions is not known. We show by gene expression microarrays that neoplastic cells of Kaposi sarcoma are closely related to lymphatic endothelial cells (LECs) and that Kaposi sarcoma herpesvirus (KSHV) infects both LECs and blood vascular endothelial cells (BECs) in vitro. The gene expression microarray profiles of infected LECs and BECs show that KSHV induces transcriptional reprogramming of both cell types. The lymphangiogenic molecules VEGF-D and angiopoietin-2 were elevated in the plasma of individuals with acquired immune deficiency syndrome and Kaposi sarcoma. These data show that the gene expression profile of Kaposi sarcoma resembles that of LECs, that KSHV induces a transcriptional drift in both LECs and BECs and that lymphangiogenic molecules are involved in the pathogenesis of Kaposi sarcoma.
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              Prognostic factors and outcome of human herpesvirus 8-associated primary effusion lymphoma in patients with AIDS.

              Primary effusion lymphoma (PEL) is a rare high-grade B-cell non-Hodgkin's lymphoma associated with Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) infection, and is mostly observed in the course of HIV infection. The prognosis is poor, with reported median survival time shorter than 6 months. To date, no prognostic factor has been identified in this subset of lymphoma. We describe here a large series of HIV-infected patients with PEL, including 28 cases diagnosed in six centers during an 11-year time period. Prognosis analysis was performed using a Cox proportional hazard regression model. Statistically significant covariates were further analyzed in a forward, stepwise multivariate model. After a median follow-up of 3.8 years (range, 10 months to 10.8 years), nine patients (32%) were still alive, and eight of them remained progression free. The median survival was 6.2 months, and the 1-year overall survival rate was 39.3%. Fourteen patients (50%) achieved complete remission, with a 1-year disease-free survival rate at 78.6%. In a multivariate analysis, only a performance status more than 2 (hazard ratio, 5.84; 95% CI, 1.76 to 19.33) and the absence of highly active antiretroviral therapy (HAART) before PEL diagnosis (hazard ratio, 3.26; 95% CI, 1.14 to 9.34) were found to be independent predictors for shorter survival. Based on a retrospective series of 28 patients, two prognostic factors were identified as being independently associated with impaired clinical outcome in HIV-related PEL--(1) a poor performance status and (2) the absence of HAART before PEL diagnosis.
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                Author and article information

                Contributors
                Role: InvestigationRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: InvestigationRole: Visualization
                Role: Formal analysisRole: MethodologyRole: Validation
                Role: ConceptualizationRole: ResourcesRole: Validation
                Role: Resources
                Role: Formal analysisRole: SoftwareRole: Validation
                Role: Funding acquisitionRole: MethodologyRole: Validation
                Role: MethodologyRole: Validation
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                12 December 2019
                December 2019
                : 15
                : 12
                : e1008174
                Affiliations
                [1 ] MOE& NHC&CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, P. R. China
                [2 ] ShengYushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P. R. China
                [3 ] Baoji Affiliated Hospital of Xi’an Medical University, Baoji & MOE Key Laboratory of Western Resources and Modern Biotechnology, College of Life Sciences, Northwest University, Xi’an, Shaanxi, China
                [4 ] School of Pharmacy, Shanghai University of Traditional Chinese Medicine & Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
                [5 ] Unit of Herpesvirus and Molecular Virology, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China
                [6 ] Beijing Computing Center, Beijing Academy of Science and Technology & Beijing Beike Deyuan Bio-Pharm Technology Company, Beijing, P. R. China
                [7 ] Expert Workstation, Baoji Central Hospital, Baoji, P. R. China
                University of Southern California, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-7743-6978
                http://orcid.org/0000-0001-6238-4511
                http://orcid.org/0000-0001-8964-1645
                http://orcid.org/0000-0002-7147-0953
                Article
                PPATHOGENS-D-19-01423
                10.1371/journal.ppat.1008174
                6932820
                31830143
                98944644-18ed-494a-9110-725db6611f8f
                © 2019 Ding et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 August 2019
                : 30 October 2019
                Page count
                Figures: 7, Tables: 0, Pages: 23
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81672015, 81971930, 81471930
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81772166
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81501739
                Award Recipient :
                Funded by: National Key Research and Development Program of China
                Award ID: 2016YFC1200400
                Award Recipient :
                Funded by: The three-year development plan project for Traditional Chinese Medicine
                Award ID: ZY2018-2020-CCCX-2001-02
                Award Recipient :
                This work was supported by the National Natural Science Foundation of China (81672015, 81971930, 81471930 to QC; 81772166 to FW, 81501739 to CZ), and the National Key Research and Development Program of China (2016YFC1200400 to QC). The three-year development plan project for Traditional Chinese Medicine (ZY2018-2020-CCCX-2001-02 to HX). QC is a scholar of New Century Excellent Talents in University of China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Oncology
                Cancer Treatment
                Research and Analysis Methods
                Animal Studies
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                2019-12-26
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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