An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

Cell Death Dis. 2021 Jul 2;12(7):663. doi: 10.1038/s41419-021-03934-y.


A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Adenoviridae / growth & development
  • Adenovirus E1 Proteins / genetics*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Line, Tumor
  • Chemotherapy, Adjuvant
  • Gene Expression Regulation, Neoplastic
  • Imidazoles / pharmacology*
  • Imidazolines / pharmacology*
  • Mesothelioma / genetics
  • Mesothelioma / metabolism
  • Mesothelioma / therapy*
  • Mesothelioma / virology
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neurofibromin 1 / genetics
  • Neurofibromin 1 / metabolism*
  • Oncolytic Virotherapy*
  • Oncolytic Viruses / genetics*
  • Oncolytic Viruses / growth & development
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Burden / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Virus Replication
  • Xenograft Model Antitumor Assays


  • Adenovirus E1 Proteins
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Imidazoles
  • Imidazolines
  • NF1 protein, human
  • Neurofibromin 1
  • Piperazines
  • RG7112
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • nutlin 3
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2