MEL-pep, an analog of melittin, disrupts cell membranes and reverses 5-fluorouracil resistance in human hepatocellular carcinoma cells

Int J Biochem Cell Biol. 2018 Aug:101:39-48. doi: 10.1016/j.biocel.2018.05.013. Epub 2018 May 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Membrane Permeability / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Fluorouracil / pharmacology*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Inhibitory Concentration 50
  • Insulin-Like Growth Factor I / pharmacology
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Melitten / analogs & derivatives
  • Melitten / pharmacology*
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Antimetabolites, Antineoplastic
  • IGF1 protein, human
  • Transcription Factor RelA
  • Melitten
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Fluorouracil