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Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2-3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells.
Int J Nanomedicine. 2016; 11:6047-6064.IJ

Abstract

Antimicrobial peptides (AMPs) have been recently evaluated as a new generation of adjuvants in cancer chemotherapy. In this study, we designed PEGylated liposomes encapsulating epirubicin as an antineoplastic agent and tilapia hepcidin 2-3, an AMP, as a multidrug resistance (MDR) transporter suppressor and an apoptosis/autophagy modulator in human cervical cancer HeLa cells. Cotreatment of HeLa cells with PEGylated liposomal formulation of epirubicin and hepcidin 2-3 significantly increased the cytotoxicity of epirubicin. The liposomal formulations of epirubicin and/or hepcidin 2-3 were found to noticeably escalate the intracellular H2O2 and O2- levels of cancer cells. Furthermore, these treatments considerably reduced the mRNA expressions of MDR protein 1, MDR-associated protein (MRP) 1, and MRP2. The addition of hepcidin 2-3 in liposomes was shown to markedly enhance the intracellular epirubicin uptake and mainly localized into the nucleus. Moreover, this formulation was also found to trigger apoptosis and autophagy in HeLa cells, as validated by significant increases in the expressions of cleaved poly ADP ribose polymerase, caspase-3, caspase-9, and light chain 3 (LC3)-II, as well as a decrease in mitochondrial membrane potential. The apoptosis induction was also confirmed by the rise in sub-G1 phase of cell cycle assay and apoptosis percentage of annexin V/propidium iodide assay. We found that liposomal epirubicin and hepcidin 2-3 augmented the accumulation of GFP-LC3 puncta as amplified by chloroquine, implying the involvement of autophagy. Interestingly, the partial inhibition of necroptosis and the epithelial-mesenchymal transition by this combination was also verified. Altogether, our results provide evidence that coincubation with PEGylated liposomes of hepcidin 2-3 and epirubicin caused programmed cell death in cervical cancer cells through modulation of multiple signaling pathways, including MDR transporters, apoptosis, autophagy, and/or necroptosis. Thus, this formulation may provide a new platform for the combined treatment of traditional chemotherapy and hepcidin 2-3 as a new adjuvant for effective MDR reversal.

Authors+Show Affiliations

Department and Institute of Pharmacology, National Yang-Ming University.Department of Biological Sciences and Technology, National University of Tainan.Department and Institute of Pharmacology, National Yang-Ming University; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.Department and Institute of Pharmacology, National Yang-Ming University.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27895479

Citation

Juang, Vivian, et al. "Cationic PEGylated Liposomes Incorporating an Antimicrobial Peptide Tilapia Hepcidin 2-3: an Adjuvant of Epirubicin to Overcome Multidrug Resistance in Cervical Cancer Cells." International Journal of Nanomedicine, vol. 11, 2016, pp. 6047-6064.
Juang V, Lee HP, Lin AM, et al. Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2-3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells. Int J Nanomedicine. 2016;11:6047-6064.
Juang, V., Lee, H. P., Lin, A. M., & Lo, Y. L. (2016). Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2-3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells. International Journal of Nanomedicine, 11, 6047-6064.
Juang V, et al. Cationic PEGylated Liposomes Incorporating an Antimicrobial Peptide Tilapia Hepcidin 2-3: an Adjuvant of Epirubicin to Overcome Multidrug Resistance in Cervical Cancer Cells. Int J Nanomedicine. 2016;11:6047-6064. PubMed PMID: 27895479.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2-3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells. AU - Juang,Vivian, AU - Lee,Hsin-Pin, AU - Lin,Anya Maan-Yuh, AU - Lo,Yu-Li, Y1 - 2016/11/15/ PY - 2016/11/30/entrez PY - 2016/11/30/pubmed PY - 2017/2/14/medline KW - antimicrobial peptide KW - apoptosis KW - autophagy KW - epirubicin KW - liposomes KW - multidrug resistance SP - 6047 EP - 6064 JF - International journal of nanomedicine JO - Int J Nanomedicine VL - 11 N2 - Antimicrobial peptides (AMPs) have been recently evaluated as a new generation of adjuvants in cancer chemotherapy. In this study, we designed PEGylated liposomes encapsulating epirubicin as an antineoplastic agent and tilapia hepcidin 2-3, an AMP, as a multidrug resistance (MDR) transporter suppressor and an apoptosis/autophagy modulator in human cervical cancer HeLa cells. Cotreatment of HeLa cells with PEGylated liposomal formulation of epirubicin and hepcidin 2-3 significantly increased the cytotoxicity of epirubicin. The liposomal formulations of epirubicin and/or hepcidin 2-3 were found to noticeably escalate the intracellular H2O2 and O2- levels of cancer cells. Furthermore, these treatments considerably reduced the mRNA expressions of MDR protein 1, MDR-associated protein (MRP) 1, and MRP2. The addition of hepcidin 2-3 in liposomes was shown to markedly enhance the intracellular epirubicin uptake and mainly localized into the nucleus. Moreover, this formulation was also found to trigger apoptosis and autophagy in HeLa cells, as validated by significant increases in the expressions of cleaved poly ADP ribose polymerase, caspase-3, caspase-9, and light chain 3 (LC3)-II, as well as a decrease in mitochondrial membrane potential. The apoptosis induction was also confirmed by the rise in sub-G1 phase of cell cycle assay and apoptosis percentage of annexin V/propidium iodide assay. We found that liposomal epirubicin and hepcidin 2-3 augmented the accumulation of GFP-LC3 puncta as amplified by chloroquine, implying the involvement of autophagy. Interestingly, the partial inhibition of necroptosis and the epithelial-mesenchymal transition by this combination was also verified. Altogether, our results provide evidence that coincubation with PEGylated liposomes of hepcidin 2-3 and epirubicin caused programmed cell death in cervical cancer cells through modulation of multiple signaling pathways, including MDR transporters, apoptosis, autophagy, and/or necroptosis. Thus, this formulation may provide a new platform for the combined treatment of traditional chemotherapy and hepcidin 2-3 as a new adjuvant for effective MDR reversal. SN - 1178-2013 UR - https://www.unboundmedicine.com/medline/citation/27895479/Cationic_PEGylated_liposomes_incorporating_an_antimicrobial_peptide_tilapia_hepcidin_2_3:_an_adjuvant_of_epirubicin_to_overcome_multidrug_resistance_in_cervical_cancer_cells_ L2 - https://dx.doi.org/10.2147/IJN.S117618 DB - PRIME DP - Unbound Medicine ER -