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Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport
P-glycoprotein affects the transport of numerous drugs including chemotherapeutic drugs vincristine sulfate (VCR) and docetaxel (DTX), and is one of the main causes for multidrug resistance. Our previous studies have shown that oxypeucedanin (OPD) can enhance the intestinal transit of puerarin and V...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222843/ https://www.ncbi.nlm.nih.gov/pubmed/30042338 http://dx.doi.org/10.3390/molecules23081841 |
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author | Dong, Wei Liao, Zhen-Gen Zhao, Guo-Wei Guan, Xue-Jing Zhang, Jing Liang, Xin-Li Yang, Ming |
author_facet | Dong, Wei Liao, Zhen-Gen Zhao, Guo-Wei Guan, Xue-Jing Zhang, Jing Liang, Xin-Li Yang, Ming |
author_sort | Dong, Wei |
collection | PubMed |
description | P-glycoprotein affects the transport of numerous drugs including chemotherapeutic drugs vincristine sulfate (VCR) and docetaxel (DTX), and is one of the main causes for multidrug resistance. Our previous studies have shown that oxypeucedanin (OPD) can enhance the intestinal transit of puerarin and VCR. However, the underlying mechanism is unclear. This study investigated the potential mechanism by which OPD improves P-gp-mediated drug transport. Molecular docking was performed to predict the binding force between OPD and P-gp and the contribution of OPD on P-gp activity. We observed the effect of OPD on the transport of VCR in MDCK-MDR1 cell monolayer and also measured the plasma pharmacokinetic parameters of DTX in the presence and absence of OPD by LC-MS/MS. Moreover, we further investigated the reversal mechanism of OPD on P-gp-mediated drug transport by determining the intracellular accumulation of Rhodamine-123 (Rh123) and P-gp ATPase activity as well as protein expression and mRNA level of P-gp. Our molecular docking results revealed that the binding force between OPD and P-gp was much lower than that between P-gp and verapamil (a P-gp substrate). The transport study in vitro indicated that OPD increased the flux of VCR across MDCK-MDR1 cell monolayer. The in vivo pharmacokinetic parameters data showed OPD increased the absorption of DTX. OPD activated P-gp ATPase activity and enhanced intracellular accumulation of Rh123 in MDCK-MDR1 cells. Western blotting and qRT-PCR outcomes indicated that OPD suppressed P-gp protein expression as well as downregulated P-gp mRNA level. Thus, OPD reverse P-gp-mediated drug transport via inhibition of P-gp activity and P-gp protein expression as well as downregulation of P-gp mRNA level. Our results suggest that OPD could reverse P-gp-mediated drug resistance in tumor cells. |
format | Online Article Text |
id | pubmed-6222843 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62228432018-11-13 Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport Dong, Wei Liao, Zhen-Gen Zhao, Guo-Wei Guan, Xue-Jing Zhang, Jing Liang, Xin-Li Yang, Ming Molecules Article P-glycoprotein affects the transport of numerous drugs including chemotherapeutic drugs vincristine sulfate (VCR) and docetaxel (DTX), and is one of the main causes for multidrug resistance. Our previous studies have shown that oxypeucedanin (OPD) can enhance the intestinal transit of puerarin and VCR. However, the underlying mechanism is unclear. This study investigated the potential mechanism by which OPD improves P-gp-mediated drug transport. Molecular docking was performed to predict the binding force between OPD and P-gp and the contribution of OPD on P-gp activity. We observed the effect of OPD on the transport of VCR in MDCK-MDR1 cell monolayer and also measured the plasma pharmacokinetic parameters of DTX in the presence and absence of OPD by LC-MS/MS. Moreover, we further investigated the reversal mechanism of OPD on P-gp-mediated drug transport by determining the intracellular accumulation of Rhodamine-123 (Rh123) and P-gp ATPase activity as well as protein expression and mRNA level of P-gp. Our molecular docking results revealed that the binding force between OPD and P-gp was much lower than that between P-gp and verapamil (a P-gp substrate). The transport study in vitro indicated that OPD increased the flux of VCR across MDCK-MDR1 cell monolayer. The in vivo pharmacokinetic parameters data showed OPD increased the absorption of DTX. OPD activated P-gp ATPase activity and enhanced intracellular accumulation of Rh123 in MDCK-MDR1 cells. Western blotting and qRT-PCR outcomes indicated that OPD suppressed P-gp protein expression as well as downregulated P-gp mRNA level. Thus, OPD reverse P-gp-mediated drug transport via inhibition of P-gp activity and P-gp protein expression as well as downregulation of P-gp mRNA level. Our results suggest that OPD could reverse P-gp-mediated drug resistance in tumor cells. MDPI 2018-07-24 /pmc/articles/PMC6222843/ /pubmed/30042338 http://dx.doi.org/10.3390/molecules23081841 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Dong, Wei Liao, Zhen-Gen Zhao, Guo-Wei Guan, Xue-Jing Zhang, Jing Liang, Xin-Li Yang, Ming Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport |
title | Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport |
title_full | Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport |
title_fullStr | Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport |
title_full_unstemmed | Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport |
title_short | Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport |
title_sort | reversal effect of oxypeucedanin on p-glycoprotein-mediated drug transport |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222843/ https://www.ncbi.nlm.nih.gov/pubmed/30042338 http://dx.doi.org/10.3390/molecules23081841 |
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