Abstract
Chemotherapy resistance represents a major obstacle in the treatment of patients with hepatocellular carcinoma (HCC). The purpose of this study was to investigate the anti-cancer effect of MEL-pep, a novel analog of the natural antibacterial peptide melittin (MEL), on human 5-fluorouracil-resistant HCC cells (BEL-7402/5-FU) and to clarify the molecular mechanisms involved in these effects. We found that MEL-pep inhibited the proliferation of BEL-7402/5-FU cells and reversed 5-FU resistance in vitro. MEL-pep directly bound to BEL-7402/5-FU cells and disrupted the cell membrane. P-glycoprotein (P-gp) plays an important role in the development of resistance to anticancer drugs. We found that MEL-pep inhibited P-gp expression and increased the intracellular accumulation of the P-gp substrate rhodamine-123 in BEL-7402/5-FU cells. Additionally, the phosphorylation of Akt and NF-κB/p65 nuclear translocation was all inhibited by MEL-pep. Insulin - like growth factor I, a phosphatidylinositol 3 kinase(PI3K) /protein kinase B(AKT) agonist, reversed MEL-pep induced P-gp suppression. Therefore, MEL-pep inhibited P-gp expression by deactivating the PI3K/Akt signaling pathway. Finally, in a BEL-7402/5-FU cell-derived xenograft tumor model in mice, we found that the intratumoral administration of MEL-pep inhibited tumor growth in a dose-dependent manner. Thus, MEL-pep could be a promising candidate in the treatment of chemotherapy resistant HCC.
Keywords:
5-Fluorouracil-resistant hepatocellular carcinoma; Cell membrane; MEL-pep; P-glycoprotein.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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Animals
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Antimetabolites, Antineoplastic / pharmacology*
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Cell Membrane Permeability / drug effects
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Fluorouracil / pharmacology*
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Gene Expression Regulation, Neoplastic*
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Humans
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Inhibitory Concentration 50
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Insulin-Like Growth Factor I / pharmacology
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Melitten / analogs & derivatives
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Melitten / pharmacology*
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Mesenchymal Stem Cells / cytology
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Mesenchymal Stem Cells / drug effects
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Mesenchymal Stem Cells / metabolism
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Mice
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Mice, Nude
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Primary Cell Culture
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Rats, Sprague-Dawley
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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ATP Binding Cassette Transporter, Subfamily B
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Antimetabolites, Antineoplastic
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IGF1 protein, human
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Transcription Factor RelA
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Melitten
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Insulin-Like Growth Factor I
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Fluorouracil