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Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of α-Tocopheryl succinate-based polyphosphoester copolymers
Chen F.-Q.1; Zhang J.-M.1,4; Fang X.-F.2; Yu H.1; Liu Y.-L.3; Li H.3; Wang Y.-T.1; Chen M.-W.1
2017
Source PublicationActa Pharmacologica Sinica
Volume38Issue:6Pages:859
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-α-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 IC 50 value of PTX was reduced from 61.51 to 0.49 μmol/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 G 2 /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. © Author(s) 2017.

KeywordA2780/ptx Cells Apoptosis Cell Cycle Arrest d-?-tocopheryl Succinate Multidrug Resistance Nanomedicines Ovarian Carcinoma P-gp Paclitaxel Redox-responsive Micelles
DOI10.1038/aps.2016.150
URLView the original
Language英语
The Source to ArticleScopus
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Cited Times [WOS]:12   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau
2.Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, United States
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
Recommended Citation
GB/T 7714
Chen F.-Q.,Zhang J.-M.,Fang X.-F.,et al. Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of α-Tocopheryl succinate-based polyphosphoester copolymers[J]. Acta Pharmacologica Sinica,2017,38(6):859.
APA Chen F.-Q..,Zhang J.-M..,Fang X.-F..,Yu H..,Liu Y.-L..,...&Chen M.-W..(2017).Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of α-Tocopheryl succinate-based polyphosphoester copolymers.Acta Pharmacologica Sinica,38(6),859.
MLA Chen F.-Q.,et al."Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of α-Tocopheryl succinate-based polyphosphoester copolymers".Acta Pharmacologica Sinica 38.6(2017):859.
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