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Pegylated phosphotidylethanolamine inhibiting P-glycoprotein expression and enhancing retention of doxorubicin in MCF7/ADR cells.
J Pharm Sci. 2011 Jun; 100(6):2267-77.JP

Abstract

The failure of the clinical treatment of cancer patients is often attributed to drug resistance of the tumor to chemotherapeutic agents. P-glycoprotein (P-gp) contributes to drug resistance via adenosine 5'-triphosphate (ATP)-dependent drug efflux pumps and is widely expressed in many human cancers. Up to date, a few of nanomaterials have shown the effects on P-gp function by different ways. To study the mechanism of the increased cytotoxicity of doxorubicin (DOX) by pegylated phosphotidylethanolamine (PEG-PE) in drug-resistant cancer cells, a series of in vitro cell assays were performed, including identification of P-gp function, quantitative studies on uptake and efflux of DOX, inhibitory effects of blank PEG-PE micelles on mRNA and protein levels of P-gp, and intracellular ATP content alteration. Finally, combining MDR-1 RNA interference (siRNA) with DOX encapsulated in PEG-PE micelles (M-DOX) to improve cytotoxicity of DOX was also studied. M-DOX showed fivefold lower the concentration that caused 50% killing tumor cell than that of free DOX in the P-gp-overexpressing MCF-7 breast cancer (MCF-7/ADR) cells. M-DOX enhanced the cellular uptake and retention of DOX in MCF-7/ADR cells. PEG-PE block molecules can inhibit P-gp expression through downregulating MDR-1 gene. Cytotoxicity of M-DOX was further improved by knocking down the MDR-1 gene using siRNA in the multidrug-resistant cells. We conclude that the increased cytotoxicity of DOX encapsulated in PEG-PE micelle is due to the reduced P-gp expression by PEG-PE block molecules, and accordingly enhancing the cellular accumulation of DOX. To overcome drug resistance of tumor cells, the combination of nanotechnology and biotechnology could be an effective strategy such as PEG-PE formed micelles and siRNA.

Authors+Show Affiliations

Protein and Peptide Pharmaceutical Laboratory, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21246559

Citation

Wang, Jing, et al. "Pegylated Phosphotidylethanolamine Inhibiting P-glycoprotein Expression and Enhancing Retention of Doxorubicin in MCF7/ADR Cells." Journal of Pharmaceutical Sciences, vol. 100, no. 6, 2011, pp. 2267-77.
Wang J, Qu H, Jin L, et al. Pegylated phosphotidylethanolamine inhibiting P-glycoprotein expression and enhancing retention of doxorubicin in MCF7/ADR cells. J Pharm Sci. 2011;100(6):2267-77.
Wang, J., Qu, H., Jin, L., Zeng, W., Qin, L., Zhang, F., Wei, X., Lu, W., Zhang, C., & Liang, W. (2011). Pegylated phosphotidylethanolamine inhibiting P-glycoprotein expression and enhancing retention of doxorubicin in MCF7/ADR cells. Journal of Pharmaceutical Sciences, 100(6), 2267-77. https://doi.org/10.1002/jps.22461
Wang J, et al. Pegylated Phosphotidylethanolamine Inhibiting P-glycoprotein Expression and Enhancing Retention of Doxorubicin in MCF7/ADR Cells. J Pharm Sci. 2011;100(6):2267-77. PubMed PMID: 21246559.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pegylated phosphotidylethanolamine inhibiting P-glycoprotein expression and enhancing retention of doxorubicin in MCF7/ADR cells. AU - Wang,Jing, AU - Qu,Hui, AU - Jin,Lingtao, AU - Zeng,Wenfeng, AU - Qin,Lei, AU - Zhang,Fayun, AU - Wei,Xiuli, AU - Lu,Wanliang, AU - Zhang,Chunling, AU - Liang,Wei, Y1 - 2011/01/18/ PY - 2010/09/24/received PY - 2010/11/16/revised PY - 2010/11/20/accepted PY - 2011/1/20/entrez PY - 2011/1/20/pubmed PY - 2011/9/10/medline SP - 2267 EP - 77 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 100 IS - 6 N2 - The failure of the clinical treatment of cancer patients is often attributed to drug resistance of the tumor to chemotherapeutic agents. P-glycoprotein (P-gp) contributes to drug resistance via adenosine 5'-triphosphate (ATP)-dependent drug efflux pumps and is widely expressed in many human cancers. Up to date, a few of nanomaterials have shown the effects on P-gp function by different ways. To study the mechanism of the increased cytotoxicity of doxorubicin (DOX) by pegylated phosphotidylethanolamine (PEG-PE) in drug-resistant cancer cells, a series of in vitro cell assays were performed, including identification of P-gp function, quantitative studies on uptake and efflux of DOX, inhibitory effects of blank PEG-PE micelles on mRNA and protein levels of P-gp, and intracellular ATP content alteration. Finally, combining MDR-1 RNA interference (siRNA) with DOX encapsulated in PEG-PE micelles (M-DOX) to improve cytotoxicity of DOX was also studied. M-DOX showed fivefold lower the concentration that caused 50% killing tumor cell than that of free DOX in the P-gp-overexpressing MCF-7 breast cancer (MCF-7/ADR) cells. M-DOX enhanced the cellular uptake and retention of DOX in MCF-7/ADR cells. PEG-PE block molecules can inhibit P-gp expression through downregulating MDR-1 gene. Cytotoxicity of M-DOX was further improved by knocking down the MDR-1 gene using siRNA in the multidrug-resistant cells. We conclude that the increased cytotoxicity of DOX encapsulated in PEG-PE micelle is due to the reduced P-gp expression by PEG-PE block molecules, and accordingly enhancing the cellular accumulation of DOX. To overcome drug resistance of tumor cells, the combination of nanotechnology and biotechnology could be an effective strategy such as PEG-PE formed micelles and siRNA. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/21246559/Pegylated_phosphotidylethanolamine_inhibiting_P_glycoprotein_expression_and_enhancing_retention_of_doxorubicin_in_MCF7/ADR_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(15)32125-0 DB - PRIME DP - Unbound Medicine ER -