Abstract:
:Adenosine triphosphate (ATP)-binding cassette (ABC) transporters play a key role in the development of multidrug resistance (MDR) in cancer cells. P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) are important proteins in this superfamily which are widely expressed on the membranes of multidrug resistance (MDR) cancer cells. Besides, upregulation of cellular autophagic responses is considered a contributing factor for MDR in cancer cells. We designed a liposome system co-encapsulating a chemotherapeutic drug (doxorubicin hydrochloride, DOX) and a typical autophagy inhibitior (chloroquine phosphate, CQ) at a weight ratio of 1:2 and investigated its drug resistance reversal mechanism. MTT assay showed that the IC50 of DOX/CQ co-encapsulated liposome in DOX-resistant human breast cancer cells (MCF7/ADR) was 4.7 ± 0.2 μM, 5.7-fold less than that of free DOX (26.9 ± 1.9 μM), whereas it was 19.5-fold in doxorubicin-resistant human acute myelocytic leukemia cancer cells (HL60/ADR) (DOX/CQ co-encapsulated liposome 1.2 ± 0.1 μM, free DOX 23.4 ± 2.8 μM). The cellular uptake of DOX increased upon addition of free CQ, indicating that CQ may interact with P-gp and MRP1; however, the expressions of P-gp and MRP1 remained unchanged. In contrast, the expression of the autophagy-related protein LC3-II increased remarkably. Therefore, the mechanism of MDR reversal may be closely related to autophagic inhibition. Evaluation of anti-tumor activity was achieved in an MCF-7/ADR multicellular tumor spheroid model and transgenic zebrafish model. DOX/CQ co-encapsulated liposome exerted a better anti-tumor effect in both models than that of liposomal DOX or DOX alone. These findings suggest that encapsulating CQ with DOX in liposomes significantly improves the sensitivity of DOX in DOX-resistant cancer cells.
journal_name
J Liposome Resjournal_title
Journal of liposome researchauthors
Gao M,Xu Y,Qiu Ldoi
10.1080/08982104.2016.1185731subject
Has Abstractpub_date
2017-06-01 00:00:00pages
151-160issue
2eissn
0898-2104issn
1532-2394journal_volume
27pub_type
杂志文章abstract:CONTEXT:The stability of liposomes in the form of dispersion is a major concern due to drug leakage and fusion or aggregation. The stability can be improved by lyophilization, but the stress induced by the lyophilization process can affect the integrity of liposomes. OBJECTIVE:The objective of this study was to evalua...
journal_title:Journal of liposome research
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journal_title:Journal of liposome research
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journal_title:Journal of liposome research
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journal_title:Journal of liposome research
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更新日期:2016-01-01 00:00:00
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更新日期:2013-12-01 00:00:00
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