Nutlin-3 overcomes arsenic trioxide resistance and tumor metastasis mediated by mutant p53 in Hepatocellular Carcinoma

Mol Cancer. 2014 May 31:13:133. doi: 10.1186/1476-4598-13-133.

Abstract

Background: Arsenic trioxide has been demonstrated as an effective anti-cancer drug against leukemia and solid tumors both in vitro and in vivo. However, recent phase II trials demonstrated that single agent arsenic trioxide was poorly effective against hepatocellular carcinoma (HCC), which might be due to drug resistance.

Methods: Mutation detection of p53 gene in arsenic trioxide resistant HCC cell lines was performed. The therapeutic effects of arsenic trioxide and Nutlin-3 on HCC were evaluated both in vitro and in vivo. A series of experiments including MTT, apoptosis assays, co-Immunoprecipitation, siRNA transfection, lentiviral infection, cell migration, invasion, and epithelial-mesenchy-mal transition (EMT) assays were performed to investigate the underlying mechanisms.

Results: The acquisition of p53 mutation contributed to arsenic trioxide resistance and enhanced metastatic potential of HCC cells. Mutant p53 (Mutp53) silence could re-sensitize HCC resistant cells to arsenic trioxide and inhibit the metastatic activities, while mutp53 overexpression showed the opposite effects. Neither arsenic trioxide nor Nutlin-3 could exhibit obvious effects against arsenic trioxide resistant HCC cells, while combination of them showed significant effects. Nutlin-3 can not only increase the intracellular arsenicals through inhibition of p-gp but also promote the p73 activation and mutp53 degradation mediated by arsenic trioxide. In vivo experiments indicated that Nutlin-3 can potentiate the antitumor activities of arsenic trioxide in an orthotopic hepatic tumor model and inhibit the metastasis to lung.

Conclusions: Acquisitions of p53 mutations contributed to the resistance of HCC to arsenic trioxide. Nutlin-3 could overcome arsenic trioxide resistance and inhibit tumor metastasis through p73 activation and promoting mutant p53 degradation mediated by arsenic trioxide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Arsenic Trioxide
  • Arsenicals / pharmacology*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Epithelial-Mesenchymal Transition / drug effects
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Imidazoles / pharmacology*
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Nude
  • Mutation
  • Neoplasm Transplantation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oxides / pharmacology*
  • Piperazines / pharmacology*
  • Signal Transduction
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Arsenicals
  • DNA-Binding Proteins
  • Imidazoles
  • Nuclear Proteins
  • Oxides
  • Piperazines
  • TP73 protein, human
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • nutlin 3
  • Arsenic Trioxide