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      Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer

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          Abstract

          Background

          Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment.

          Methods

          The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry).

          Results

          In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14–1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer.

          Conclusions

          The efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumor compound for gastric cancer.

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          Most cited references51

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          Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.

          Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large "areas" of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths). © 2014 UICC.
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            Gastric cancer

            Gastric cancer is the fifth most common cancer and the third most common cause of cancer death globally. Risk factors for the condition include Helicobacter pylori infection, age, high salt intake, and diets low in fruit and vegetables. Gastric cancer is diagnosed histologically after endoscopic biopsy and staged using CT, endoscopic ultrasound, PET, and laparoscopy. It is a molecularly and phenotypically highly heterogeneous disease. The main treatment for early gastric cancer is endoscopic resection. Non-early operable gastric cancer is treated with surgery, which should include D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial branches). Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers. Advanced gastric cancer is treated with sequential lines of chemotherapy, starting with a platinum and fluoropyrimidine doublet in the first line; median survival is less than 1 year. Targeted therapies licensed to treat gastric cancer include trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or pembrolizumab (anti-PD-1 third line).
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              ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.

              Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.
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                Author and article information

                Contributors
                hcui@swu.edu.cn , hongjuan.cui@gmail.com
                Journal
                J Exp Clin Cancer Res
                J Exp Clin Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                30 October 2020
                30 October 2020
                2020
                : 39
                : 230
                Affiliations
                [1 ]GRID grid.263906.8, State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, , Southwest University, ; #1, Tiansheng Rd., Beibei District, Chongqing, 400716 China
                [2 ]GRID grid.263906.8, Cancer center, Medical Research Institute, , Southwest University, ; Chongqing, 400716 China
                [3 ]Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716 China
                [4 ]GRID grid.263906.8, Engineering Research Center for Cancer Biomedical and Translational Medicine, , Southwest University, ; Chongqing, 400716 China
                [5 ]GRID grid.410726.6, ISNI 0000 0004 1797 8419, Chongqing General Hospital, , University of Chinese Academy of Sciences, ; Chongqing, 400014 China
                [6 ]GRID grid.440260.4, The Fifth Hospital of Shijiazhuang, ; Shijiazhuang, 050021 China
                [7 ]GRID grid.452209.8, The Third Hospital of Hebei Medical University, ; Shijiazhuang, 050051 China
                Article
                1743
                10.1186/s13046-020-01743-3
                7602321
                33126914
                6367bcce-2037-4222-8e91-9c954dd18036
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

                History
                : 28 June 2020
                : 19 October 2020
                Funding
                Funded by: National Key Research and Development Program of China
                Award ID: No. 2016YFC1302204
                Award ID: No. 2017YFC1308600
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: No. 81872071
                Award ID: No. 81672502
                Award ID: No. 31802142
                Award ID: No. 81902664
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100005230, Natural Science Foundation of Chongqing;
                Award ID: No. cstc2019jcyj-zdxmX0033
                Award Recipient :
                Funded by: Fundamental Research Funds for Central Universities of the Central South University (CN)
                Award ID: No. XDJK2019C089
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100012459, Chongqing Graduate Student Research Innovation Project;
                Award ID: No.CYB18105
                Award ID: No. CYS18124
                Award Recipient :
                Funded by: Fundamental Research Funds for the Central Universities
                Award ID: No. SWU120009
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                gastric cancer,lycorine hydrochloride,mcl1,fbxw7,apoptosis,cell cycle,drug-resistance,pdx model

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