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Co-encapsulation of chrysophsin-1 and epirubicin in PEGylated liposomes circumvents multidrug resistance in HeLa cells.
Chem Biol Interact. 2015 Dec 05; 242:13-23.CB

Abstract

Chrysophsin-1, an amphipathic alpha-helical antimicrobial peptide, is isolated from the gills of the red sea bream and possesses different structure and mechanism(s) in comparison with traditional multidrug resistance (MDR) modulators. For the purpose of reducing off-target normal cell toxicity, it is rational to incorporate chrysophsin-1 and epirubicin in a PEGylated liposomal formulation. In the present study, we report a multifunctional liposomes with epirubicin as an antineoplastic agent and an apoptosis inducer, as well as chrysophsin-1 as a MDR transporter inhibitor and an apoptosis modulator in human cervical cancer HeLa cells. Co-incubation of HeLa cells with PEGylated liposomal formulation of epirubicin and chrysophsin-1 resulted in a significant increase in the cytotoxicity of epirubicin. The liposomal formulations of epirubicin and/or chrysophsin-1 were shown to considerably improve the intracellular H2O2 and O2(-) levels of HeLa cells. Furthermore, these treatments were found to extensively reduce mRNA expression levels of MDR1, MRP1, and MRP2. The addition of chrysophsin-1 in liposomes was demonstrated to substantially enhance the intracellular accumulation of epirubicin in HeLa cells. Moreover, the PEGylated liposomes of epirubicin and chrysophsin-1 were also found to significantly increase the mRNA expressions of p53, Bax, and Bcl-2. The ratio of Bax to Bcl-2 was noticeably amplified in the presence of these formulations. Apoptosis induction was also validated by chromatin condensation, a reduction in mitochondrial membrane potential, the increased sub-G1 phase of cell cycle, and more populations of apoptosis using annexin V/PI assay. These formulations were verified to increase the activity and mRNA expression levels of caspase-9 and caspases-3. Collectively, our findings provide the first evidence that cotreatment with free or liposomal chrysophsin-1 and epirubicin leads to cell death in human cervical cancer cells through the ROS-mediated inhibition of P-gp and MRPs and concerted activation of mitochondrial apoptosis pathway. Thus, chrysophsin-1 represents a potential antimicrobial peptide to function as a new generation of MDR-reversing agent to enhance the activity of cancer chemotherapeutics.

Authors+Show Affiliations

Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. Electronic address: yulilo@ym.edu.tw.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

26335193

Citation

Lo, Yu-Li, and Wei-Chen Tu. "Co-encapsulation of Chrysophsin-1 and Epirubicin in PEGylated Liposomes Circumvents Multidrug Resistance in HeLa Cells." Chemico-biological Interactions, vol. 242, 2015, pp. 13-23.
Lo YL, Tu WC. Co-encapsulation of chrysophsin-1 and epirubicin in PEGylated liposomes circumvents multidrug resistance in HeLa cells. Chem Biol Interact. 2015;242:13-23.
Lo, Y. L., & Tu, W. C. (2015). Co-encapsulation of chrysophsin-1 and epirubicin in PEGylated liposomes circumvents multidrug resistance in HeLa cells. Chemico-biological Interactions, 242, 13-23. https://doi.org/10.1016/j.cbi.2015.08.023
Lo YL, Tu WC. Co-encapsulation of Chrysophsin-1 and Epirubicin in PEGylated Liposomes Circumvents Multidrug Resistance in HeLa Cells. Chem Biol Interact. 2015 Dec 5;242:13-23. PubMed PMID: 26335193.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Co-encapsulation of chrysophsin-1 and epirubicin in PEGylated liposomes circumvents multidrug resistance in HeLa cells. AU - Lo,Yu-Li, AU - Tu,Wei-Chen, Y1 - 2015/09/01/ PY - 2015/03/19/received PY - 2015/07/04/revised PY - 2015/08/28/accepted PY - 2015/9/4/entrez PY - 2015/9/4/pubmed PY - 2016/5/4/medline KW - Antimicrobial peptide KW - Apoptosis KW - Epirubicin KW - Liposomes KW - Multidrug resistance KW - Reactive oxygen species SP - 13 EP - 23 JF - Chemico-biological interactions JO - Chem Biol Interact VL - 242 N2 - Chrysophsin-1, an amphipathic alpha-helical antimicrobial peptide, is isolated from the gills of the red sea bream and possesses different structure and mechanism(s) in comparison with traditional multidrug resistance (MDR) modulators. For the purpose of reducing off-target normal cell toxicity, it is rational to incorporate chrysophsin-1 and epirubicin in a PEGylated liposomal formulation. In the present study, we report a multifunctional liposomes with epirubicin as an antineoplastic agent and an apoptosis inducer, as well as chrysophsin-1 as a MDR transporter inhibitor and an apoptosis modulator in human cervical cancer HeLa cells. Co-incubation of HeLa cells with PEGylated liposomal formulation of epirubicin and chrysophsin-1 resulted in a significant increase in the cytotoxicity of epirubicin. The liposomal formulations of epirubicin and/or chrysophsin-1 were shown to considerably improve the intracellular H2O2 and O2(-) levels of HeLa cells. Furthermore, these treatments were found to extensively reduce mRNA expression levels of MDR1, MRP1, and MRP2. The addition of chrysophsin-1 in liposomes was demonstrated to substantially enhance the intracellular accumulation of epirubicin in HeLa cells. Moreover, the PEGylated liposomes of epirubicin and chrysophsin-1 were also found to significantly increase the mRNA expressions of p53, Bax, and Bcl-2. The ratio of Bax to Bcl-2 was noticeably amplified in the presence of these formulations. Apoptosis induction was also validated by chromatin condensation, a reduction in mitochondrial membrane potential, the increased sub-G1 phase of cell cycle, and more populations of apoptosis using annexin V/PI assay. These formulations were verified to increase the activity and mRNA expression levels of caspase-9 and caspases-3. Collectively, our findings provide the first evidence that cotreatment with free or liposomal chrysophsin-1 and epirubicin leads to cell death in human cervical cancer cells through the ROS-mediated inhibition of P-gp and MRPs and concerted activation of mitochondrial apoptosis pathway. Thus, chrysophsin-1 represents a potential antimicrobial peptide to function as a new generation of MDR-reversing agent to enhance the activity of cancer chemotherapeutics. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/26335193/Co_encapsulation_of_chrysophsin_1_and_epirubicin_in_PEGylated_liposomes_circumvents_multidrug_resistance_in_HeLa_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0009-2797(15)30051-X DB - PRIME DP - Unbound Medicine ER -