Reversal of multidrug resistance by Marsdenia tenacissima and its main active ingredients polyoxypregnanes
To, Kenneth K. W.2,4; Wu, Xu3,4; Yin, Chun3,4; Chai, Stella3,4; Yao, Sheng1,4,5; Kadioglu, Onat6; Efferth, Thomas6; Ye, Yang1,4,5; Lin, Ge3,4
刊名JOURNAL OF ETHNOPHARMACOLOGY
2017-05-05
卷号203页码:110-119
关键词ABCG2 Multidrug resistance Marsdenia tenacissima MRP1 P-glycoprotein Polyoxypregnane compounds
ISSN号0378-8741
DOI10.1016/j.jep.2017.03.051
文献子类Article
英文摘要Ethnopharmacological relevance: Multidrug resistance (MDR) of cancer is often associated with the over expression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), multidrug resistance associated protein-1 (MRP-1) and breast cancer resistance protein (BCRP or ABCG2), in cancer cells, which facilitates the active efflux of a wide variety of chemotherapeutic drugs out of the cells. Marsdenia tenacissima is a traditional Chinese medicinal herb that has long been clinically used for treatment of cancers, particularly in combinational use with anticancer drugs. Polyoxypregnanes (POPs) are identified as main constituents of this herb, and three of them have been reported to exhibit P-gp modulatory effect and thus reverse MDR. Therefore, it is of great necessity to investigate more POPs that have potential to reverse transporters-mediated MDR. Aim of the study: We aimed to identify POPs as the chemical basis responsible for circumventing ABC transporters-mediated MDR by M. tenacissima. Materials and methods: The MDR reversal effects of M. tenacissima crude extract together with a series of isolated POPs were evaluated on several MDR cancer cell lines that overexpress P-gp, MRP1 or ABCG2. The activities of P-gp, MRP1 and ABCG2 were determined by the flow cytometry-based substrate efflux assay. Molecular docking of POPs to a three-dimensional human P-gp homology structure was also performed. Results: The crude extract of M. tenacissima was firstly found to circumvent P-gp-mediated MDR. Then, 11 polyoxypregnane compounds (POPs) isolated from this herb were found to overcome P-gp-, MRP1- and/or ABCG2-mediated MDR. Further mechanistic study delineated that the reversal of MDR by these POPs was due to significant increase in the intracellular concentrations of the substrate anticancer drugs via their inhibition of different ABC transporter-mediated efflux activities. Furthermore, molecular docking revealed that POPs with P-gp modulatory effect bound to P-gp and fitted well into the cavity between the alpha and beta subunit of P-gp via forming hydrogen bonds. In addition, several key structural determinants for inhibition of P-gp, MRP1 or ABCG2 by POPs were illustrated. Conclusions: Our findings advocated the rational use of M. tenacissima to enhance efficacies of conventional anticancer drugs in tumors with ABC drug transporters-mediated MDR. Furthermore, 11 POPs were found to contribute to MDR reversal effect of M. tenacissima via inhibition of different ABC efflux transporters.
资助项目Health and Medical Research Fund from Food and Health Bureau, HKSAR[08090481] ; Chinese University of Hong Kong[2041448] ; CUHK[3132968] ; Seed Fund for Joint Establishments from School of Biomedical Science, CUHK[00000000]
WOS关键词P-GLYCOPROTEIN INHIBITOR ; IN-VIVO ; ORAL BIOAVAILABILITY ; BRAIN PENETRATION ; BREAST-CARCINOMA ; HALF-TRANSPORTER ; DRUG-BINDING ; CELL-LINES ; CANCER ; PROTEIN
WOS研究方向Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine
语种英语
出版者ELSEVIER IRELAND LTD
WOS记录号WOS:000401214700012
内容类型期刊论文
源URL[http://119.78.100.183/handle/2S10ELR8/272670]  
专题天然药物化学研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Ye, Yang; Lin, Ge
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China;
2.Chinese Univ Hong Kong, Fac Med, Sch Pharm, Hong Kong, Hong Kong, Peoples R China;
3.Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China;
4.Chinese Acad Sci, Joint Res Lab Promoting Globalizat Tradit Chinese, Shatin, Hong Kong, Peoples R China;
5.Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Chem Dept, 555 Zu Chong Zhi Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China;
6.Johannes Gutenberg Univ Mainz, Dept Pharmaceut Biol, Mainz, Germany
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To, Kenneth K. W.,Wu, Xu,Yin, Chun,et al. Reversal of multidrug resistance by Marsdenia tenacissima and its main active ingredients polyoxypregnanes[J]. JOURNAL OF ETHNOPHARMACOLOGY,2017,203:110-119.
APA To, Kenneth K. W..,Wu, Xu.,Yin, Chun.,Chai, Stella.,Yao, Sheng.,...&Lin, Ge.(2017).Reversal of multidrug resistance by Marsdenia tenacissima and its main active ingredients polyoxypregnanes.JOURNAL OF ETHNOPHARMACOLOGY,203,110-119.
MLA To, Kenneth K. W.,et al."Reversal of multidrug resistance by Marsdenia tenacissima and its main active ingredients polyoxypregnanes".JOURNAL OF ETHNOPHARMACOLOGY 203(2017):110-119.
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