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      13-[CH 2CO-Cys-(Bzl)-OBzl]-Berberine: Exploring The Correlation Of Anti-Tumor Efficacy With ROS And Apoptosis Protein


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          The discovery of novel derivative of berberine (BBR) having higher anti-tumor activity in vivo is of clinical importance. In this profile, 13-[CH 2CO-Cys-(Bzl)-OBzl]-berberine (13-Cys-BBR) was prepared for related assays.


          The object of preparation and evaluation is to show the advantages of 13-Cys-BBR over BBR in both in vitro and in vivo anti-tumor actions, furthermore to correlate the proliferation of cancer cells with ROS formation and anti-apoptosis protein (XIAP) expression inside cancer cells.


          Transwell chamber was used to simulate the intestinal and cell wall for bioavailability evaluation; MTT assay was used to evaluate the in vitro anti-proliferation activity; fluorescein isothiocyanate content was used to represent ROS level in HCT-8 cells; Western blot assay was used to quantify the expression of XIAP, caspase-3, and poly ADP-ribose polymerase in HCT-8 cells; and S180 mouse model was used to evaluate the in vivo anti-tumor activity.


          In vitro the IC 50 values (~15–40 μM) of 13-Cys-BBR against the proliferation of eight cancer cell lines were significantly lower than those of BBR (~25–140 μM); the content of ROS formed inside HCT-8 cells treated by 13-Cys-BBR was ~3.44-folds higher than that inside HCT-8 cells treated by BBR; the expression of XIAP in HCT-8 cells treated by 13-Cys-BBR was ~1.21-folds lower than that in HCT-8 cells treated by BBR; the tumor weight of S180 mice orally treated by 2 μmol/kg/day of 13-Cys-BBR (~1.5 g) was significantly lower than that of S180 mice orally treated by 2 μmol/kg/day of BBR (~2.5 g); and the active pocket of XIAP was more suitable for 13-Cys-BBR than for BBR.


          The anti-tumor action correlates with ROS and apoptosis protein, which suggests 13-Cys-BBR is a promising candidate for preclinical study.

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          Most cited references26

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          Berberine ameliorates chronic relapsing dextran sulfate sodium-induced colitis in C57BL/6 mice by suppressing Th17 responses

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            Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma.

            Hepatocellular carcinoma (HCC) is an invasive cancer with a high rate of recurrence and metastasis. Agents with anti-proliferative as well as anti-metastatic activity will be ideal for effective treatment. Here, we demonstrated that berberine, an isoquinoline alkaloid, harbored potent anti-metastatic and anti-proliferative activities in vivo. Using an orthotopic model of HCC (MHCC-97L), which spontaneously develops lung metastases (one of the most common sites of HCC metastasis), we found that berberine treatment (10mg/kg/2days) significantly reduced lung metastasis from the liver tumors by ~85% (quantitated by bioluminescence emitted from lung metastases). Histological examination also confirmed the reduced incidence and number of lung metastases in berberine-treated mice. Furthermore, berberine effectively suppressed extra-tumor invasion of the primary HCC implant into the surrounding normal liver tissue, illustrating its potent anti-metastatic action in vivo. Consistent with previous reports in other cancer, berberine's anti-tumor activity was accompanied by suppression of cellular proliferation, invasiveness and HIF-1α/VEGF signaling. Strikingly, further mechanistic investigation revealed that berberine exerted profound inhibitory effect on the expression of Id-1, which is a key regulator for HCC development and metastasis. Berberine could suppress the transcription level of Id-1 through inhibiting its promotor activity. Specific downregulation of Id-1 by knocking down its RNA transcripts in HCC cells inhibited cellular growth, invasion and VEGF secretion, demonstrating the functional relevance of Id-1 downregulation induced by berberine. Lastly, berberine's anti-proliferative and anti-invasive activities could be partially rescued by Id-1 overexpression in HCC models, revealing a novel anti-cancer/anti-invasive mechanism of berberine via Id-1 suppression.
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              Berberine and Coptidis Rhizoma as potential anticancer agents: Recent updates and future perspectives.

              The antineoplastic property of Coptidis Rhizoma and berberine was correlated with its traditional use of clearing internal fire, removing damp-heat and counteracting toxic pathogens.

                Author and article information

                Onco Targets Ther
                Onco Targets Ther
                OncoTargets and therapy
                05 December 2019
                : 12
                : 10651-10662
                [1 ]Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University , Beijing 100069, People’s Republic of China
                [2 ]Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University , Beijing 100069, People’s Republic of China
                [3 ]Beijing Laboratory of Biomedical Materials and Key Laboratory of Biomedical Materials of Natural Macromolecules, Beijing University Of Chemical Technology , Beijing 100026, People’s Republic of China
                Author notes
                Correspondence: Shiqi Peng; Ming Zhao Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University , No. 10, Youanmenwaixitoutiao, Fengtai District, Beijing100069, People’s Republic of ChinaTel +86 1083911528; +86 1083911535Fax +86 1083911528; +86 1083911533 Email sqpeng@bjmu.edu.cn; mingzhao@bjmu.edu.cn
                © 2019 Li et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 10, References: 27, Pages: 12
                Original Research

                Oncology & Radiotherapy

                berberine, 13-position modification, anti-tumor, ros, xiap


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