- Articles Online
- About Journal
- For Authors
- 个人中心
- 退出登录
浏览全部资源
扫码关注微信
- Articles Online
- Online First
- Current issue
- Archive
- Collections
- Special Issues
- About Journal
- About the Journal
- Editorial Board
- Awards
- Inclusion
- Subscriptions
- For Authors
- Editorial Policy
- Manuscript Review
- Ethical Review
- Interest Conflict
- Data Sharing
- Contact Us
- Interest Conflict
- Charge and Payments
- Data Sharing
Anticancer Effect and Molecular Docking Mechanism of 24-OH-panaxadiol
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 25, Issue 6, Pages: 81-88(2019)
- 作者机构：
1.山西医科大学，太原 030001；
2.吉林大学 药学院，长春 130021；
3.哈佛大学 医学院 麻省总医院 移植研究中心，波士顿 02129
- 作者简介：
- 基金信息：
DOI：10.13422/j.cnki.syfjx.20190622
CLC： R22;R242;R2-031;R285.5Received：10 July 2018，
Published Online：12 December 2018，
Published：20 March 2019
- 稿件说明：
移动端阅览
Qian ZHENG, Zhao-hui WANG, Zeng QI, et al. Anticancer Effect and Molecular Docking Mechanism of 24-OH-panaxadiol[J]. Chinese journal of experimental traditional medical formulae, 2019, 25(6): 81-88.
Qian ZHENG, Zhao-hui WANG, Zeng QI, et al. Anticancer Effect and Molecular Docking Mechanism of 24-OH-panaxadiol[J]. Chinese journal of experimental traditional medical formulae, 2019, 25(6): 81-88. DOI： 10.13422/j.cnki.syfjx.20190622.
摘要
目的：
2
为研究人参皂苷20(
S
)-达玛-20，25-环氧-3
β
，12
β
，24
α
-三醇(24-OH-PD)对多种癌细胞的增殖抑制及诱导凋亡作用并探讨其作用机制。
方法：
2
采用噻唑蓝(MTT)比色法或CellTiter Glo®发光试验检测24-OH-PD在不同质量浓度(12.5，25，50，100 mg·L
－1
)，不同作用时间(24，48，72 h)下对CCRF-CEM
Jeko-1
M14
MD-MBA-231癌细胞的增殖抑制作用，并与20(
R
)-Rg
3
，20(
S
)-Rh
2
进行比较。采用流式细胞术检测24-OH-PD对以上4种癌细胞的凋亡诱导作用。采用药物设计平台薛定谔Maestro 6.7软件对癌症相关的40种蛋白与24-OH-PD进行分子对接研究。
结果：
2
24-OH-PD对4种癌细胞均具有明显的细胞活性抑制作用，且具有时间、剂量依赖性。24-OH-PD对CCRF-CEM，Jeko-1，M14，MD-MBA-231细胞作用48 h时半抑制浓度(IC
50
)分别为25.36，39.29，21.74，19.35 mg·L
－1
，与20(
S
)-Rh
2
作用效果相似(IC
50
分别为23.35
65.79
18.95
19.67 mg·L
－1
)；远远强于20(
R
)-Rg
3
，仅对Jeko-1细胞有抑制作用(IC
50
49.5 mg·L
－1
)。磷脂结合蛋白V/碘化吡啶(Annexin V/PI)双染实验结果显示，24-OH-PD对4种细胞均具有不同程度的促凋亡作用(
P
<
0.05)，且具有剂量依赖关系。分子对接实验表明32个癌症相关蛋白中有11个能够与24-OH-PD对接成功，包括嘌呤核苷磷酸化酶(PNP)，蛋白络氨酸激酶，蛋白激酶C(PKC)，B淋巴细胞瘤基因-2(Bcl-2)，B淋巴细胞瘤基因-xl (Bcl-xl)，含半胱氨酸的天冬氨酸蛋白水解酶-8等，表明24-OH-PD的抗肿瘤作用可能与直接作用于这些蛋白相关。
结论：
2
人参皂苷24-OH-PD对CCRF-CEM，M14，MD-MBA-231，Jeko-1癌细胞具有增殖抑制作用，其机制可能与PNP，PKC等蛋白相关；同时24-OH-PD还具有诱导癌细胞凋亡的作用，机制可能与Bcl-2，Bcl-xl等蛋白相关。
Abstract
Objective:
2
To investigate the effect of ginsenoside 20(
S
)
25-epoxydammarane-3
β
12
β
24
α
-triol (24-OH-panaxadiol
24-OH-PD) on inhibiting proliferation and inducing apoptosis of tumor cells
and explore its mechanism of action.
Method:
2
The inhibitory effect of 24-OH-PD (12.5
25
50
100 mg·L
-1
) on proliferation of CCRF-CEM
M14
MD-MBA-231 and Jeko-1 cells with different treatment periods (24
48
72 h) was evaluated by methylthiazolyldiphenyl-tetrazolium bromide (MTT)assay and CellTiter Glo® test
and the results were then compared with 20(
R
)-Rg
3
and 20(
S
)-Rh
2
.Flow cytometry was used to detect cell apoptosis caused by 24-OH-PD. Besides
the potential anticancer mechanism was studied by docking analysis with 40 cancer related proteins and 24-OH-PD by using drug design platform Schrodinger Maestro 6.7 Software.
Result:
2
24-OH-PD inhibited the proliferation of all the 4 cancer cell lines significantly in a time and dosage dependent manner. The IC
50
value of 24-OH-PD on CCRF-CEM
Jeko-1
M14
and MD-MBA-231 cell lines was 25.36
39.29
21.74
and 19.35 mg·L-1
respectively
similar to 20(
S
)-Rh
2
(IC
50
23.35
65.79
18.95
19.67 mg·L
-1
) and much better than 20(
R
)-Rg
3
(only effective for Jeko-1 cells
IC
50
49.5 mg·L
-1
). Annexin V/PI double staining experiment showed that 24-OH-PD could also induce apoptosis of the 4 kinds of cancer cells (
P
<
0.05) in a dose-dependent manner. In the molecular docking test
24-OH-PD was docked successfully with 11 tumor related proteins
including purine nucleoside phosphorylase (PNP)
protein tyrosine kinase
protein kinase C (PKC)
B-cell lymphoma-2 (Bcl-2)
B-cell lymphoma-xl (Bcl-xl) and Caspase-8 et al
which demonstrated that the anti-tumor effect of 24-OH-PD may be related to the direct effects on these proteins.
Conclusion:
2
24-OH-PD could inhibit cell proliferation and induce apoptosis for CCRF-CEM
M14
MD-MBA-231 and Jeko-1 cell lines
which may through directly acting on Bcl-2
Bcl-xl
and other proteins.
关键词
Keywords
references
CHEN X J , ZHANG X J , SHUI Y M , et al . Anticancer activities of protopanaxadiol- and protopanaxatriol-type ginsenosides and their metabolites [J]. Evid Based Compl Alt Med , 2016 , doi: 10.1155/2016/5738694 doi:10.1155/2016/5738694 .
Ota T , Maeda M , Odashima S , et al . G1 phase-specific suppression of the Cdk2 activity by ginsenoside Rh 2 in cultured murine cells [J]. Life Sci , 1997 , 60 ( 2 ): PL39 - 44 .
ZHANG Q , KANG X , YANG B , et al . Antiangiogenic effect of capecitabine combined with ginsenoside Rg 3 on breast cancer in mice [J]. Cancer Biother Radiopharm , 2008 , 23 ( 5 ): 647 - 653 .
LIU T , ZHAO L , ZHANG Y , et al . Ginsenoside 20(S)-Rg 3 targets HIF-1 α to block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells [J]. PLoS One , 2014 , 9 ( 9 ): e103887 .
WU R , RU Q , CHEN L , et al . Stereospecificity of ginsenoside Rg 3 in the promotion of cellular immunity in Hepatoma H22-bearing mice [J]. J Food Sci , 2014 , 79 ( 7 ): 1430 - 1435 .
权恺 ， 刘群 ， 李萍 ， 等 . 人参皂苷抗癌活性的最新研究进展 [J]. 医学研究生学报 ， 2015 , 28 ( 4 ): 427 - 431 .
ZHENG Q , LI Z , LIU J , et al . Two new dammarane-type triterpene sapogenins from Chinese red ginseng [J]. Nat Prod Res , 2016 , 30 ( 1 ): 95 - 99 .
WANG Z , Pratts S G , ZHANG H , et al . Treg depletion in non-human primates using a novel diphtheria toxin-based anti-human CCR4 immunotoxin [J]. Mol Oncol , 2016 , 10 ( 4 ): 553 - 565 .
Stamos J , Sliwkowski M X , Eigenbrot C. Structure of the EGF receptor kinase domain alone and in complex with a4-anilinoquinazoline inhibitor [J]. J Biol Chem , 2002 , 75 ( 36 ): 2091 - 2092 .
Sarkar J , Nandy S K , Chowdhury A , et al . Inhibition of MMP-9 by green tea catechins and prediction of their interaction by molecular docking analysis [J]. Biomed Pharmacother , 2016 , 84 : 340 - 347 .
Revelant G , Al-Lakkis-Wehbe M , Schmitt M , et al . Exploring S1 plasticity and probing S1’ subsite of mammalian Aminopeptidase N/CD13 with highly potent and selective aminobenzosuberone inhibitors [J]. Bioorgan Med Chem , 2015 , 23 ( 13 ): 3192 - 3207 .
Sansen S , Yano J K , Reynald R L , et al . Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2 [J]. J Biol Chem , 2007 , 282 ( 19 ): 14348 - 14355 .
Vinh N B , Devine S M , Munoz L , et al . Design, synthesis, and biological evaluation of tetra-substituted thiophenes as inhibitors of p38 α MAPK [J]. Chemistryopen , 2015 , 4 ( 1 ): 56 - 64 .
Singh S , Das T , Awasthi M , et al . DNA topoisomerase-directed anticancerous alkaloids: ADMET-based screening, molecular docking, and dynamics simulation [J]. Biotechnol Appl Bioc , 2015 , 63 ( 1 ): 125 - 137 .
Sartaj T , Mehvash Z , Mohd A , et al . Synthesis and characterization of Cu(Ⅱ)-based anticancer chemotherapeutic agent targeting topoisomerase I α ： in vitro DNA binding, pBR322 cleavage, molecular docking studies and cytotoxicity against human cancer cell lines [J]. Eur J Med Chem , 2014 , 74 ( 5 ): 509 - 523 .
Gogoi D , Baruah V J , Chaliha A K , et al . 3D pharmacophore-based virtual screening, docking and density functional theory approach towards the discovery of novel human epidermal growth factor receptor-2 (HER2) [J]. J Theor Biol , 2016 , 411 : 68 - 80 .
WANG Y , CHENG F X , YUAN X L , et al . Dihydropyrazole derivatives as telomerase inhibitors: structure-based design, synthesis, SAR and anticancer evaluation in vitro and in vivo [J]. Euro J Med Chem , 2016 , 112 : 231 - 251 .
Dufe V T , Ingner D , Heby O , et al . A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane [J]. Biochem J , 2007 , 405 ( 2 ): 261 - 268 .
苏敬雷 . 中药穿心莲和冬凌草的计算药理学研究 [D]. 郑州 ： 郑州大学 ， 2015 .
Fatima S , Jatavath M B , Bathini R , et al . Multiple receptor conformation docking, dock pose clustering and 3D QSAR studies on human poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors [J]. J Recept Sig Transd , 2014 , 34 ( 5 ): 417 - 430 .
Abdel Latif N A , Batran R Z , Khedr M A , et al . 3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: Synthesis, molecular modeling and QSAR studies [J]. Bioorg Chem , 2016 , 67 : 116 - 129 .
Sathishkumar N , Sathiyamoorthy S , Ramya M , et al . Molecular docking studies of anti-apoptotic Bcl-2, Bcl-xl, and MCL-1 proteins with ginsenosides from Panax ginseng [J]. J Enzyme Inhib Med Chem , 2012 , 27 ( 5 ): 685 - 692 .
Pottel J , Therrien E , Gleason J L , et al . Docking ligands into flexible and solvated macromolecules. 6.development and application to the docking of HDACs and other Zinc metalloenzymes inhibitors [J]. J Cheml Inf Model , 2013 , 54 ( 1 ): 254 - 65 .
Balachandran C , Sangeetha B , Duraipandiyan V , et al . A flavonoid isolated from Streptomyces sp. (ERINLG-4) induces apoptosis in human lung cancer A549 cells through p53 and cytochrome C release caspase dependant pathway [J]. Chem-Biol Interact , 2014 , 224 : 24 - 35 .
Leong K H , Looi C Y , Loong X M , et al . Cycloart-24-ene-26-ol-3-one, a new cycloartane isolated from leaves of aglaia exima triggers tumour Necrosis factor-receptor 1-mediated Caspase-dependent apoptosis in colon cancer cell line [J]. PLoS One , 2016 , 11 ( 4 ): e0152652 .
Saloahen O M H , Tochowicz A , Pozzi C , et al . Hotspots in an obligate homodimeric anticancer target. Structural and functional effects of interfacial mutations in human thymidylate synthase [J]. J Med Chem , 2015 , 58 ( 8 ): 3572 - 3581 .
WANG Z , WANG N , HAN S , et al . Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway [J]. PLoS One , 2013 , 8 ( 7 ): e68566 .
ZHU W , WANG W , XU S , et al . Design, synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2，3-b]pyridine moiety as c-Met inhibitors [J]. Bioorgan Med Chem , 2016 , 24 ( 8 ): 1749 - 1756 .
Naresh K M , Thunuguntla V B S C , Veeramachaneni G K , et al . Molecular characterization of human ABHD2 as TAG lipase and ester hydrolase [J]. Bioscience Rep , 2016 , 36 ( 4 ): 1 - 11 .
Keerthy H K , Mohan C D , Siveen K S , et al . Novel synthetic biscoumarins target tumor necrosis factor- α in hepatocellular carcinoma in vitro and in vivo [J]. J Biol Chem , 2014 , 289 ( 46 ): 31879 - 31890 .
Kadioglu O , CAO J , Saeed M E M , et al . Targeting epidermal growth factor receptors and downstream signaling pathways in cancer by phytochemicals [J]. Target Oncol , 2015 , 10 ( 3 ): 337 - 353 .
戴国梁 ， 马世堂 ， 刘史佳 ， 等 . 二咖啡酰奎宁酸与人血浆阿司匹林酯酶的分子对接 [J]. 中成药 ， 2014 , 36 ( 9 ): 1901 - 1905 .
Kojima S , Chiyomaru T , Kawakami K , et al . Tumour suppressors miR-1 and miR-133a target the oncogenic function of purine nucleoside phosphorylase (PNP) in prostate cancer [J]. Brit J Cancer , 2011 , 106 ( 2 ): 405 - 413 .
Popovich D G , Kitts D D. Structure-function relationship exists for ginsenosides in reducing cell proliferation and inducing apoptosis in the human leukemia (THP-1) cell line [J]. Arch Biochem Biophys , 2002 , 406 ( 1 ): 1 - 8 .
DONG H , BAI L P , WONG V K , et al . The in vitro structure-related anti-cancer activity of ginsenosides and their derivatives [J]. Molecules , 2011 , 16 ( 12 ): 10619 - 10630 .
刘存 ， 刘丽娟 ， 周超 ， 等 . 基于“蛋白质相互作用网络-分子对接技术-体外实验”三维模式分析青黛对慢性粒细胞白血病的作用机制 [J]. 中国实验方剂学杂志 ， 2017 , 23 ( 21 ): 206 - 211 .
Arpaia E , Benveniste P , Di Cristofano A , et al . Mitochondrial basis for immune deficiency: evidence from purine nucleoside phosphorylase-deficient mice [J]. J Exp Med , 2000 , 191 ( 12 ): 2197 - 2208 .
Ravandi F , Gandhi V. Novel purine nucleoside analogues for T-cell-lineage acute lymphoblastic leukaemia and lymphoma [J]. Expert Opin Investig Drugs , 2006 , 15 ( 12 ): 1601 - 1613 .
吴洁 ， 倪沛洲 ， 凌霞 . 蛋白激酶C的研究进展 [J]. 中国药物化学杂志 ， 2001 , 11 ( 3 ): 182 - 186 .
You W K , Sennino B , Williamson C W , et al . VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer [J]. Cancer Res , 2011 , 71 ( 14 ): OF1 - 11 .
Min J K , Kim J H , Cho Y L , et al . 20 (S)-Ginsenoside Rg 3 prevents endothelial cell apoptosis via inhibition of a mitochondrial caspase pathway [J]. Biochem Biophy Res Co , 2006 , 349 ( 3 ): 987 - 994 .
刘德明 ， 周春燕 ， 吴嘉思 ， 等 . 大黄素通过线粒体通路诱导HepG2细胞凋亡 [J]. 中国实验方剂学杂志 ， 2018 , 24 ( 3 ): 104 - 108 .
0
Views
14
下载量
1
CSCD
- L-PDFDownload
- BibTeXDownload
- EndnoteDownload
- RefMan Download
- NoteExpressDownload
- NoteFirstDownload
Publicity Resources
Related Articles
Related Author
Related Institution
AI问答- Postal code：100700
- Tel：010-84076882 Email：syfjx_2010@188.com
- Technical support is provided by Beijing Founder electronics co., LTD 京ICP备11006657号-10
京公网安备11010802024621 - It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
- Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.
