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      Hypericin-photodynamic therapy inhibits the growth of adult T-cell leukemia cells through induction of apoptosis and suppression of viral transcription

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          Abstract

          Background

          Adult T-cell leukemia (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). ATL carries a poor prognosis due to chemotherapy resistance. Thus, it is urgent to develop new treatment strategies. Hypericin (HY) is a new-type of photosensitizer in the context of photodynamic therapy (PDT) due to its excellent photosensitizing properties and anti-tumor activities.

          Results

          In the present study, we investigated the efficacy of hypericin in ATL cells. Clinically achievable concentrations of hypericin in association with PDT induced the inhibition of cell proliferation in ATL cell lines with minimal effect on peripheral blood CD4 + T lymphocytes. Moreover, hypericin-PDT treatment caused apoptosis and G2/M phase cell cycle arrest in leukemic cells. Western blot analyses revealed that hypericin-PDT treatment resulted in downregulation of Bcl-2 and enhanced the expression of Bad, cytochrome C, and AIF. Cleavage of caspases-3/-7/-9/-8, Bid, and PARP was increased in hypericin-PDT-treated ATL cells. In a luciferase assay, hypericin-PDT treatment was able to activate the promoter activity of Bax and p53, resulting in enhanced expression of Bax and p53 proteins. Finally, hypericin-PDT treatment suppressed the expression of viral protein HBZ and Tax by blocking the promoter activity via HTLV-1 5′LTR and 3′LTR.

          Conclusions

          Our results revealed that hypericin-PDT is highly effective against ATL cells by induction of apoptosis and suppression of viral transcription. These studies highlight the promising use of hypericin-PDT as a targeted therapy for ATL.

          Electronic supplementary material

          The online version of this article (10.1186/s12977-019-0467-0) contains supplementary material, which is available to authorized users.

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          Most cited references 45

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          Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation.

          It has been 30 years since a 'new' leukaemia termed adult T-cell leukaemia (ATL) was described in Japan, and more than 25 years since the isolation of the retrovirus, human T-cell leukaemia virus type 1 (HTLV-1), that causes this disease. We discuss HTLV-1 infectivity and how the HTLV-1 Tax oncoprotein initiates transformation by creating a cellular environment favouring aneuploidy and clastogenic DNA damage. We also explore the contribution of a newly discovered protein and RNA on the HTLV-1 minus strand, HTLV-1 basic leucine zipper factor (HBZ), to the maintenance of virus-induced leukaemia.
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            Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting.

            Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-lymphocytic malignancy associated with a retrovirus designated human T-cell lymphotropic virus type I (HTLV-1). The diversity in clinical features and prognosis of patients with this disease has led to its subclassification into the following four categories: acute, lymphoma, chronic, and smoldering types. The chronic and smoldering subtypes are considered indolent and are usually managed with watchful waiting until disease progression, analogous to the management of some patients with chronic lymphoid leukemia (CLL) or other indolent histology lymphomas. Patients with aggressive ATL generally have a poor prognosis because of multidrug resistance of malignant cells, a large tumor burden with multiorgan failure, hypercalcemia, and/or frequent infectious complications as a result of a profound T-cell immunodeficiency. Under the sponsorship of the 13th International Conference on Human Retrovirology: HTLV, a group of ATL researchers joined to form a consensus statement based on established data to define prognostic factors, clinical subclassifications, and treatment strategies. A set of response criteria specific for ATL reflecting a combination of those for lymphoma and CLL was proposed. Clinical subclassification is useful but is limited because of the diverse prognosis among each subtype. Molecular abnormalities within the host genome, such as tumor suppressor genes, may account for these diversities. A treatment strategy based on the clinical subclassification and prognostic factors is suggested, including watchful waiting approach, chemotherapy, antiviral therapy, allogeneic hematopoietic stem-cell transplantation (alloHSCT), and targeted therapies.
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              Photodynamic therapy (PDT): a short review on cellular mechanisms and cancer research applications for PDT.

              Photodynamic therapy (PDT) has been used for many years, but it is only now becoming widely accepted and utilized. Originally it was developed as a tumor therapy and some of its most successful applications are for non-malignant diseases. This article provides a broad review of different parameters used and mechanisms instituted in PDT such as photosensitizers (PS), photochemistry and photophysics, cellular localization, cellular signaling, cell metabolism and modes of cell death that operate on a cellular level, as well as photosensitizer pharmacokinetics, biodistribution, tumor localization and modes of tumor destruction. These specific cellular mechanisms are most commonly applied in PDT and for the most part are often researched and exploited. If the combination of these specific parameters and mechanisms can be optimized within PDT it could possibly be used as a suitable alternative for the treatment and management of specific cancers.
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                Author and article information

                Contributors
                xll0518@zjnu.cn
                136352327@qq.com
                873787232@qq.com
                392290843@qq.com
                736627738@qq.com
                1003430336@qq.com
                630206743@qq.com
                shaolinxiang@zjnu.cn
                tjzhao@zjnu.cn
                Journal
                Retrovirology
                Retrovirology
                Retrovirology
                BioMed Central (London )
                1742-4690
                19 February 2019
                19 February 2019
                2019
                : 16
                Affiliations
                [1 ]ISNI 0000 0001 2219 2654, GRID grid.453534.0, College of Chemistry and Life Sciences, , Zhejiang Normal University, ; 688 Yingbin Road, Jinhua, 321004 Zhejiang China
                [2 ]ISNI 0000 0000 8895 903X, GRID grid.411404.4, Biomedical Department, , Huaqiao University, ; Quanzhou, China
                Article
                467
                10.1186/s12977-019-0467-0
                6381730
                30782173
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31470262
                Award ID: 31200128
                Award Recipient :
                Funded by: Zhejiang Province Public Welfare Technology Application Research Project
                Award ID: 2015C33149
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Microbiology & Virology

                apoptosis, atl, htlv-1, photodynamic therapy, hypericin

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