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Reversing multidrug resistance in Caco-2 by silencing MDR1, MRP1, MRP2, and BCL-2/BCL-xL using liposomal antisense oligonucleotides.
PLoS One. 2014; 9(3):e90180.Plos

Abstract

Multidrug resistance (MDR) is a major impediment to chemotherapy. In the present study, we designed antisense oligonucleotides (ASOs) against MDR1, MDR-associated protein (MRP)1, MRP2, and/or BCL-2/BCL-xL to reverse MDR transporters and induce apoptosis, respectively. The cationic liposomes (100 nm) composed of N-[1-(2,3-dioleyloxy)propyl]-n,n,n-trimethylammonium chloride and dioleoyl phosphotidylethanolamine core surrounded by a polyethylene glycol (PEG) shell were prepared to carry ASOs and/or epirubicin, an antineoplastic agent. We aimed to simultaneously suppress efflux pumps, provoke apoptosis, and enhance the chemosensitivity of human colon adenocarcinoma Caco-2 cells to epirubicin. We evaluated encapsulation efficiency, particle size, cytotoxicity, intracellular accumulation, mRNA levels, cell cycle distribution, and caspase activity of these formulations. We found that PEGylated liposomal ASOs significantly reduced Caco-2 cell viability and thus intensified epirubicin-mediated apoptosis. These formulations also decreased the MDR1 promoter activity levels and enhanced the intracellular retention of epirubicin in Caco-2 cells. Epirubicin and ASOs in PEGylated liposomes remarkably decreased mRNA expression levels of human MDR1, MRP1, MRP2, and BCL-2. The combined treatments all significantly increased the mRNA expressions of p53 and BAX, and activity levels of caspase-3, -8, and -9. The formulation of epirubicin and ASOs targeting both pump resistance of MDR1, MRP1, and MRP2 and nonpump resistance of BCL-2/BCL-xL demonstrated more superior effect to all the other formulations used in this study. Our results provide a novel insight into the mechanisms by which PEGylated liposomal ASOs against both resistance types act as activators to epirubicin-induced apoptosis through suppressing MDR1, MRP1, and MRP2, as well as triggering intrinsic mitochondrial and extrinsic death receptor pathways. The complicated regulation of MDR highlights the necessity for a multifunctional approach using an effective delivery system, such as PEGylated liposomes, to carry epirubicin and ASOs as a potent nanomedicine for improving the clinical efficacy of chemotherapy.

Authors+Show Affiliations

Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan.Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan.

Pub Type(s)

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

Language

eng

PubMed ID

24637737

Citation

Lo, Yu-Li, and Yu Liu. "Reversing Multidrug Resistance in Caco-2 By Silencing MDR1, MRP1, MRP2, and BCL-2/BCL-xL Using Liposomal Antisense Oligonucleotides." PloS One, vol. 9, no. 3, 2014, pp. e90180.
Lo YL, Liu Y. Reversing multidrug resistance in Caco-2 by silencing MDR1, MRP1, MRP2, and BCL-2/BCL-xL using liposomal antisense oligonucleotides. PLoS One. 2014;9(3):e90180.
Lo, Y. L., & Liu, Y. (2014). Reversing multidrug resistance in Caco-2 by silencing MDR1, MRP1, MRP2, and BCL-2/BCL-xL using liposomal antisense oligonucleotides. PloS One, 9(3), e90180. https://doi.org/10.1371/journal.pone.0090180
Lo YL, Liu Y. Reversing Multidrug Resistance in Caco-2 By Silencing MDR1, MRP1, MRP2, and BCL-2/BCL-xL Using Liposomal Antisense Oligonucleotides. PLoS One. 2014;9(3):e90180. PubMed PMID: 24637737.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reversing multidrug resistance in Caco-2 by silencing MDR1, MRP1, MRP2, and BCL-2/BCL-xL using liposomal antisense oligonucleotides. AU - Lo,Yu-Li, AU - Liu,Yu, Y1 - 2014/03/17/ PY - 2013/10/28/received PY - 2014/01/27/accepted PY - 2014/3/19/entrez PY - 2014/3/19/pubmed PY - 2015/1/7/medline SP - e90180 EP - e90180 JF - PloS one JO - PLoS One VL - 9 IS - 3 N2 - Multidrug resistance (MDR) is a major impediment to chemotherapy. In the present study, we designed antisense oligonucleotides (ASOs) against MDR1, MDR-associated protein (MRP)1, MRP2, and/or BCL-2/BCL-xL to reverse MDR transporters and induce apoptosis, respectively. The cationic liposomes (100 nm) composed of N-[1-(2,3-dioleyloxy)propyl]-n,n,n-trimethylammonium chloride and dioleoyl phosphotidylethanolamine core surrounded by a polyethylene glycol (PEG) shell were prepared to carry ASOs and/or epirubicin, an antineoplastic agent. We aimed to simultaneously suppress efflux pumps, provoke apoptosis, and enhance the chemosensitivity of human colon adenocarcinoma Caco-2 cells to epirubicin. We evaluated encapsulation efficiency, particle size, cytotoxicity, intracellular accumulation, mRNA levels, cell cycle distribution, and caspase activity of these formulations. We found that PEGylated liposomal ASOs significantly reduced Caco-2 cell viability and thus intensified epirubicin-mediated apoptosis. These formulations also decreased the MDR1 promoter activity levels and enhanced the intracellular retention of epirubicin in Caco-2 cells. Epirubicin and ASOs in PEGylated liposomes remarkably decreased mRNA expression levels of human MDR1, MRP1, MRP2, and BCL-2. The combined treatments all significantly increased the mRNA expressions of p53 and BAX, and activity levels of caspase-3, -8, and -9. The formulation of epirubicin and ASOs targeting both pump resistance of MDR1, MRP1, and MRP2 and nonpump resistance of BCL-2/BCL-xL demonstrated more superior effect to all the other formulations used in this study. Our results provide a novel insight into the mechanisms by which PEGylated liposomal ASOs against both resistance types act as activators to epirubicin-induced apoptosis through suppressing MDR1, MRP1, and MRP2, as well as triggering intrinsic mitochondrial and extrinsic death receptor pathways. The complicated regulation of MDR highlights the necessity for a multifunctional approach using an effective delivery system, such as PEGylated liposomes, to carry epirubicin and ASOs as a potent nanomedicine for improving the clinical efficacy of chemotherapy. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24637737/Reversing_multidrug_resistance_in_Caco_2_by_silencing_MDR1_MRP1_MRP2_and_BCL_2/BCL_xL_using_liposomal_antisense_oligonucleotides_ L2 - https://dx.plos.org/10.1371/journal.pone.0090180 DB - PRIME DP - Unbound Medicine ER -