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Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of alpha-tocopheryl succinate-based polyphosphoester copolymers
Chen, Feng-qian1; Zhang, Jin-ming1,4; Fang, Xie-fan2; Yu, Hua1; Liu, Yu-ling3; Li, Hui3; Wang, Yi-tao1; Chen, Mei-wan1
2017-06
Source PublicationACTA PHARMACOLOGICA SINICA
ISSN1671-4083
Volume38Issue:6Pages:859-873
Abstract

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle in achieving the therapeutic benefits of paclitaxel (PTX) in the treatment of human ovarian carcinoma. This study is aimed to develop an efficient PTX drug delivery approach to overcome MDR. Redox-responsive micelles consisting of amphiphilic polymers containing disulfide linkages, ie, poly (phosphate ester)-SS-D-alpha-tocopheryl succinate (POPEA-SS-TOS, PSST) were prepared. PTX-loaded PSST micelles (PTX/PSST-M) designed to display synergistic functions, including reversible inhibition of P-gp, intracellular redox-sensitive release and potent anticancer activities. The average size of PTX/PSST-M was 68.1 +/- 4.9 nm. The encapsulated PTX was released quickly through redox-triggered dissociation of micelles. The inhibition of P-gp activity and enhanced cellular accumulation of the PSST micelles were validated. PTX/PSST-M showed significantly increased cytotoxicity against PTX-resistant human ovarian cancer A2780/PTX cells: when the cells were treated with PTX/PSST-M for 48 h, the equivalent IC50 value of PTX was reduced from 61.51 to 0.49 mu mol/L. The enhanced cytotoxic effects of PTX/PSST-M against A2780/PTX cells were attributed to their synergistic effects on reducing the mitochondrial transmembrane potential, ATP depletion, ROS production, and activation of apoptotic pathways. Furthermore, PTX/PSST-M significantly increased cell apoptosis/necrosis and cell cycle arrest at the G2/M phase in A2780/PTX cells. These results demonstrate that the redox-responsive PSST micelles inhibit P-gp activity and have a good potential to effectively reverse PTX resistance in human ovarian carcinoma cells by activating intrinsic apoptotic pathways.

KeywordOvarian Carcinoma Paclitaxel Multidrug Resistance Nanomedicines D-alpha-tocopheryl Succinate Redox-responsive Micelles P-gp Apoptosis Cell Cycle Arrest A2780/ptx Cells
DOIhttp://doi.org/10.1038/aps.2016.150
URLView the original
Indexed BySCI
Language英语
WOS Research AreaChemistry ; Pharmacology & Pharmacy
WOS SubjectChemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS IDWOS:000402526900011
PublisherACTA PHARMACOLOGICA SINICA
The Source to ArticleWOS
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Cited Times [WOS]:9   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorChen, Mei-wan
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
2.Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
3.Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing 100700, China
4.College of Pharmacy,Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Chen, Feng-qian,Zhang, Jin-ming,Fang, Xie-fan,et al. Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of alpha-tocopheryl succinate-based polyphosphoester copolymers[J]. ACTA PHARMACOLOGICA SINICA,2017,38(6):859-873.
APA Chen, Feng-qian.,Zhang, Jin-ming.,Fang, Xie-fan.,Yu, Hua.,Liu, Yu-ling.,...&Chen, Mei-wan.(2017).Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of alpha-tocopheryl succinate-based polyphosphoester copolymers.ACTA PHARMACOLOGICA SINICA,38(6),859-873.
MLA Chen, Feng-qian,et al."Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of alpha-tocopheryl succinate-based polyphosphoester copolymers".ACTA PHARMACOLOGICA SINICA 38.6(2017):859-873.
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