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The Use of a Liposomal Formulation Incorporating an Antimicrobial Peptide from Tilapia as a New Adjuvant to Epirubicin in Human Squamous Cell Carcinoma and Pluripotent Testicular Embryonic Carcinoma Cells.
Int J Mol Sci. 2015 Sep 18; 16(9):22711-34.IJ

Abstract

This study aims to explore the effects and mechanisms of hepcidin, a potential antimicrobial peptide from Tilapia, and epirubicin (Epi), an antineoplastic agent, on the generation of reactive oxygen species (ROS) and link the ROS levels to the reversal mechanisms of multidrug resistance (MDR) by epirubicin and hepcidin in human squamous cell carcinoma SCC15 and human embryonal carcinoma NT2D1 cells. The cells, pretreated with hepcidin, epirubicin, or a combination of these compounds in PEGylated liposomes, were used to validate the molecular mechanisms involved in inhibiting efflux transporters and inducing apoptosis as evaluated by cytotoxicity, intracellular accumulation, mRNA levels, cell cycle distribution, and caspase activity of this combination. We found that hepcidin significantly enhanced the cytotoxicity of epirubicin in liposomes. The co-incubation of epirubicin with hepcidin in liposomes intensified the ROS production, including hydrogen peroxide and superoxide free radicals. Hepcidin significantly increased epirubicin intracellular uptake into NT2D1 and SCC15 cells, as supported by the diminished mRNA expressions of MDR1, MDR-associated protein (MRP) 1, and MRP2. Hepcidin and/or epirubicin in liposomes triggered apoptosis, as verified by the reduced mitochondrial membrane potential, increased sub-G1 phase of cell cycle, incremental populations of apoptosis using annexin V/PI assay, and chromatin condensation. As far as we know, this is the first example showing that PEGylated liposomal TH1-5 and epirubicin gives rise to cell death in human squamous carcinoma and testicular embryonic carcinoma cells through the reduced epirubicin efflux via ROS-mediated suppression of P-gp and MRPs and concomitant initiation of mitochondrial apoptosis pathway. Hence, hepcidin in PEGylated liposomes may function as an adjuvant to anticancer drugs, thus demonstrating a novel strategy for reversing MDR.

Authors+Show Affiliations

Department and Institute of Pharmacology, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Taipei 112, Taiwan. yulilo@ym.edu.tw.Department of Biological Sciences and Technology, National University of Tainan, Tainan 700, Taiwan. roselee6688@yahoo.com.tw.Department of Biological Sciences and Technology, National University of Tainan, Tainan 700, Taiwan. luyu2013@hotmail.com.tw.

Pub Type(s)

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

Language

eng

PubMed ID

26393585

Citation

Lo, Yu-Li, et al. "The Use of a Liposomal Formulation Incorporating an Antimicrobial Peptide From Tilapia as a New Adjuvant to Epirubicin in Human Squamous Cell Carcinoma and Pluripotent Testicular Embryonic Carcinoma Cells." International Journal of Molecular Sciences, vol. 16, no. 9, 2015, pp. 22711-34.
Lo YL, Lee HP, Tu WC. The Use of a Liposomal Formulation Incorporating an Antimicrobial Peptide from Tilapia as a New Adjuvant to Epirubicin in Human Squamous Cell Carcinoma and Pluripotent Testicular Embryonic Carcinoma Cells. Int J Mol Sci. 2015;16(9):22711-34.
Lo, Y. L., Lee, H. P., & Tu, W. C. (2015). The Use of a Liposomal Formulation Incorporating an Antimicrobial Peptide from Tilapia as a New Adjuvant to Epirubicin in Human Squamous Cell Carcinoma and Pluripotent Testicular Embryonic Carcinoma Cells. International Journal of Molecular Sciences, 16(9), 22711-34. https://doi.org/10.3390/ijms160922711
Lo YL, Lee HP, Tu WC. The Use of a Liposomal Formulation Incorporating an Antimicrobial Peptide From Tilapia as a New Adjuvant to Epirubicin in Human Squamous Cell Carcinoma and Pluripotent Testicular Embryonic Carcinoma Cells. Int J Mol Sci. 2015 Sep 18;16(9):22711-34. PubMed PMID: 26393585.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Use of a Liposomal Formulation Incorporating an Antimicrobial Peptide from Tilapia as a New Adjuvant to Epirubicin in Human Squamous Cell Carcinoma and Pluripotent Testicular Embryonic Carcinoma Cells. AU - Lo,Yu-Li, AU - Lee,Hsin-Pin, AU - Tu,Wei-Chen, Y1 - 2015/09/18/ PY - 2015/07/25/received PY - 2015/09/09/revised PY - 2015/09/11/accepted PY - 2015/9/23/entrez PY - 2015/9/24/pubmed PY - 2016/7/22/medline KW - antimicrobial peptide KW - apoptosis KW - epirubicin KW - liposomes KW - multidrug resistance KW - reactive oxygen species SP - 22711 EP - 34 JF - International journal of molecular sciences JO - Int J Mol Sci VL - 16 IS - 9 N2 - This study aims to explore the effects and mechanisms of hepcidin, a potential antimicrobial peptide from Tilapia, and epirubicin (Epi), an antineoplastic agent, on the generation of reactive oxygen species (ROS) and link the ROS levels to the reversal mechanisms of multidrug resistance (MDR) by epirubicin and hepcidin in human squamous cell carcinoma SCC15 and human embryonal carcinoma NT2D1 cells. The cells, pretreated with hepcidin, epirubicin, or a combination of these compounds in PEGylated liposomes, were used to validate the molecular mechanisms involved in inhibiting efflux transporters and inducing apoptosis as evaluated by cytotoxicity, intracellular accumulation, mRNA levels, cell cycle distribution, and caspase activity of this combination. We found that hepcidin significantly enhanced the cytotoxicity of epirubicin in liposomes. The co-incubation of epirubicin with hepcidin in liposomes intensified the ROS production, including hydrogen peroxide and superoxide free radicals. Hepcidin significantly increased epirubicin intracellular uptake into NT2D1 and SCC15 cells, as supported by the diminished mRNA expressions of MDR1, MDR-associated protein (MRP) 1, and MRP2. Hepcidin and/or epirubicin in liposomes triggered apoptosis, as verified by the reduced mitochondrial membrane potential, increased sub-G1 phase of cell cycle, incremental populations of apoptosis using annexin V/PI assay, and chromatin condensation. As far as we know, this is the first example showing that PEGylated liposomal TH1-5 and epirubicin gives rise to cell death in human squamous carcinoma and testicular embryonic carcinoma cells through the reduced epirubicin efflux via ROS-mediated suppression of P-gp and MRPs and concomitant initiation of mitochondrial apoptosis pathway. Hence, hepcidin in PEGylated liposomes may function as an adjuvant to anticancer drugs, thus demonstrating a novel strategy for reversing MDR. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/26393585/The_Use_of_a_Liposomal_Formulation_Incorporating_an_Antimicrobial_Peptide_from_Tilapia_as_a_New_Adjuvant_to_Epirubicin_in_Human_Squamous_Cell_Carcinoma_and_Pluripotent_Testicular_Embryonic_Carcinoma_Cells_ L2 - https://www.mdpi.com/resolver?pii=ijms160922711 DB - PRIME DP - Unbound Medicine ER -