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Anti-Tumor Xanthones from Garcinia Nujiangensis Suppress Proliferation, and Induce Apoptosis Via PARP, PI3K/AKT/Mtor, and MAPK/E

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Anti-Tumor Xanthones from Garcinia Nujiangensis Suppress Proliferation, and Induce Apoptosis Via PARP, PI3K/AKT/Mtor, and MAPK/E Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Anti-Tumor Xanthones from Garcinia nujiangensis Suppress Proliferation, and Induce Apoptosis via PARP, PI3K/AKT/mTOR, and MAPK/ERK Signaling Pathways in Human Ovarian Cancers Cells This article was published in the following Dove Press journal: Drug Design, Development and Therapy Zhongyan Tang 1,* Background: Ovarian cancer (OC) is a serious public health concern in the world. It is Lihua Lu2,* important to develop novel drugs to inhibit OC. Zhengxiang Xia3 Purpose: This study investigated the isolation, elucidation, efficiency, molecular docking, and pharmaceutical mechanisms of xanthones isolated from Garcinia nujiangensis. 1Department of Emergency and Critical Care Medicine, Jin Shan Hospital, Fudan Methods: Xanthones were isolated, and purified by different chromatography, including University, Shanghai 201508, People’s silica gel, reversed-phase silica gel (ODS-C18), and semipreparative HPLC, then identified 2 Republic of China; Department of by analysis of their spectral data. Three xanthones were estimated for their efficiency on the Neonatology, International Peace Maternity and Child Health Hospital, human OC cells HEY and ES-2. 2 was found to be the most potent cytotoxic xanthones of School of Medicine, Shanghai Jiao Tong those tested. Further, its mechanisms of action were explored by molecular docking, cell University, Shanghai 200030, People’s apoptosis, and Western blotting analysis. Republic of China; 3Department of Pharmacy, School & Hospital of Results: Bioassay-guided fractionation of the fruits of Garcinia nujiangensis led to the separa­ Stomatology, Shanghai Engineering tion of a new xanthone named nujiangexanthone G (1) and two known xanthones. Among these, Research Center of Tooth Restoration isojacareubin (2) exhibited the most potent cytotoxic compound against the HEY and ES-2 cell and Regeneration, Tongji University, Shanghai 200072, People’s Republic of lines. The analysis of Western blot suggested that 2 inhibited OC via regulating the PARP, PI3K/ China AKT/mTOR, and ERK/MAPK signal pathways in the HEY cell lines. *These authors contributed equally to Conclusion: In conclusion, isojacareubin (2) might be a potential drug for the treatment of this work OC. Keywords: Garcinia nujiangensis, xanthone, ovarian cancer; OC, molecular docking, apoptosis Introduction Ovarian cancer (OC) is the deadliest form of gynaecological malignancy in the world, with the increasing number of new cases and deaths in the last year.1 Due to a lack of evident symptoms in the early stage of OC, most women diagnosed with it are at an advanced stage of the disease and this can lead to high mortality rates.2 Cytoreductive surgery and chemotherapy are the first-line treatment for OC, how­ ever, the chemotherapy has side and toxic effects, most of the patients diagnosed with advanced OC survive no more than 5 years. Therefore, novel therapeutic strategies are urgently required which can improve survival in OC patients.3 Poly (ADP-ribose) polymerase (PARP), a family of proteins involved in DNA Correspondence: Zhengxiang Xia damage repair, genomic stability, and programmed cell death. The development Tel +8621-66315500 4 Email [email protected] of PARP inhibitors (PARPi) has succeed in the treatment of OC. However, submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 3965–3976 3965 DovePress © 2020 Tang 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 http://doi.org/10.2147/DDDT.S258811 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). Tang et al Dovepress resistance to PARPi is one of the major problems. were performed on an Agilent 500M-NMR spectrometer. Combination therapy is useful for enhancing therapeutics High-resolution mass spectrometry was carried on in the treatment of complex diseases (such as OC).5 The a Waters Q-TOF Premier instrument (Micromass MS phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian Technologies, Manchester, UK) loaded with an ESI target of rapamycin (mTOR) and mitogen-activated pro­ source. Column chromatography was done with silica gel tein kinase (MAPK)/extracellular signal-regulated kinase (200–300 mesh, Qingdao Haiyang Chemical Co., Ltd.), (ERK) signaling pathways play an important role in the reversed-phase C18 silica gel (250 mesh, Merck), and regulation of cell survival, growth, and proliferation. Sephadex LH-20 (Pharmacia). An Agilent 1260 machine Irregularities in the major components of those signaling was loaded with a C18 column (Zorbax SB, 4.6 × 250 mm, pathways leads to human cancers including OC.6 Natural 5 μm) was applied for HPLC analysis. 3-(4, 5-Dimethyl- products regulates multiple signal pathways involved in 2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide was OC will be a prospect agent. obtained from Sigma-Aldrich (St Louis, MO, USA). Natural product xanthones (dibenzo-γ-pyrones) con­ Dulbecco's Modified Eagle’s Medium (DMEM), penicillin stitutes a significant class of oxygenated heterocycles and streptomycin, fetal bovine serum, and 0.05% trypsin and occurs as secondary metabolites in microorganisms was purchased from GibcoBRL (Grand Island, NY, USA). and plants.7 This kind of metabolites showed numerous Compounds were dissolved in dimethyl sulphoxide pharmacological activities such as anti-cancer,8 anti- (DMSO). The values of OD were carried on a microplate oxidant,9 diuresis and saluresis,10 hepatoprotective,11 reader (Bio-Rad, Hercules, CA, USA). Antibodies cleaved anti-gout,12 anti-inflammatory,13 anti-diabetes,14 and Cas-3, cleaved PARP, Bcl-2, Bax, p-PI3K, p-AKT, gastroprotective.15 Recently, these xanthones easily p-mTOR, p-ERK1, ERK1, p-MEK, p-C-Raf, GAPDH, incorporated into micro-molecules attributing to intri­ and Enhanced chemiluminescent (ECL) plus reagent kit guing biological activities had drew attention from were obtained from Beyotime Institute of Biotechnology phytochemical,16 organic synthesis,17,18 and pharmaco­ (Shanghai, China). The cell morphology was visualized by logical endeavors.19 Xanthones from the genus Garcinia the use of an optical microscope (Olympus, Japan). had structural diversity and exhibited significant biolo­ gical activity.20 Garcinia nujiangensis is a Chinese Plant Material endemic species, grown in Nujiang, Yunnan province The fruits of G. nujiangensis (Clusiaceae), were collected in China. Our previous study on the leaves, twigs, and in Nujiang, Yunnan P.R. China, in September 2018, iden­ fruits of this plant led to the discovery of several cyto­ tified by Prof. Yuanchuan Zhou, traditional Chinese med­ toxic xanthones.21–23 In our continuing research on new icine of Yunnan university. A voucher specimen (NJ. 028) anti-OC compounds from traditional Chinese medicine, was deposited in the lab of Shanghai Engineering the extract of the fruits of G. nujiangensis exhibited Research Center of Tooth Restoration and Regeneration, inhibitory effects on the HEY cell lines. Bioassay- Tongji University. guided separation of G. nujiangensis led to the isolation of a new xanthone, nujiangexanthone G (1), and two Extraction and Isolation known xanthones. In this article we report the isolation, The fruits of G. nujiangensis (1200 g) were cut into pieces, separation, structure elucidation, and bioassay evaluation and extracted with acetone at the temperature of 25 °C of these xanthones, the potential proteins involved in the three times. The extract (132 g) was suspended in water (2 progress of OC regulated by 2 screened by molecular L) and extracted with hexane, ethyl acetate, and n-ButOH docking, which was demonstrated by the Western blot successively. The ethyl acetate portion (24 g) was sub­ analysis. jected to a silica gel column (200–300 mesh, 400 g), using a gradient of dichloromethane–acetone (from 1:0 to 0:1) to afford six fractions (A–F). Fr. C (338 mg) showed moder­ Materials and Methods ate cytotoxic activity against the HEY cell lines. It was General subjected to ODS-C18 using a gradient of methanol–water HPLC data was performed on an Agilent 1200 instrument (from 65:35 to 95:5) as eluant to obtain three subfractions loaded with ultraviolet detector. Optical rotations were C1–C3. Fr.C1 (30 mg) was subjected to semi-preparative examined on a JASCO P-1020 polarimeter. NMR data HPLC using methanol–water (55:45 including 0.1% TFA, 3966 submit your manuscript | www.dovepress.com Drug Design, Dev elopment and Therapy 2020:14 DovePress Dovepress Tang et al 3 mL/min) to afford compounds 2 (12 mg) and 3 (8 mg). manufacturer’s instruction. Stained cells (1 × 106 per reaction) Fr.B2 (80 mg) was subject to semi-preparative HPLC were tested on a flow cytometer (FACSCalibur, Becton using methanol–water (65:35, including 0.1% TFA, Dickinson). Flow cytometry assay was repeated 3 times. 3 mL/min) to obtain compound 1 (5 mg). Molecular Docking Cell Culture The 2D chemical structure of the xanthones were Human OC cell lines HEY and ES2, and human bronchial drawn and the 2D coordinates were converted into the epithelioid cell lines 16HBE were purchased from 3D format in Chemdraw 10. The Gasteiger-Huckel Beyotime Institute of Biotechnology (Shanghai, China). charges were computed using the FF12SB method of Cells were cultured in DMEM medium including 10% Chimera 1.10.1. The molecular targets were obtained fetal bovine serum. Cells were preserved at 37 °C in from the Protein Data Bank (PDB) according to the best resolution value. The co-crystalized ligands were a humidified environment under 5% CO2. used to analyze the active site on the molecular targets.
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