Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed

Cancer Gene Ther. 2012 Mar;19(3):218-28. doi: 10.1038/cgt.2011.86. Epub 2012 Jan 6.

Abstract

The majority of malignant mesothelioma possesses the wild-type p53 gene with a homologous deletion of the INK4A/ARF locus containing the p14(ARF) and the p16(INK4A) genes. We examined whether forced expression of p53 inhibited growth of mesothelioma cells and produced anti-tumor effects by a combination of cisplatin (CDDP) or pemetrexed (PEM), the first-line drugs for mesothelioma treatments. Transduction of mesothelioma cells with adenoviruses bearing the p53 gene (Ad-p53) induced phosphorylation of p53, upregulated Mdm2 and p21 expression levels and decreased phosphorylation of pRb. The transduction generated cleavage of caspase-8 and -3, but not caspase-9. Cell cycle analysis showed increased G0/G1- or G2/M-phase populations and subsequently sub-G1 fractions, depending on cell types and Ad-p53 doses. Transduction with Ad-p53 suppressed viability of mesothelioma cells and augmented the growth inhibition by CDDP or PEM mostly in a synergistic manner. Intrapleural injection of Ad-p53 and systemic administration of CDDP produced anti-tumor effects in an orthotopic animal model. These data collectively suggest that Ad-p53 is a possible agent for mesothelioma in combination with the first-line chemotherapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Caspases / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cisplatin / administration & dosage
  • Enzyme Activation
  • Female
  • Genes, p53*
  • Glutamates / administration & dosage
  • Guanine / administration & dosage
  • Guanine / analogs & derivatives
  • Humans
  • Mesothelioma / drug therapy*
  • Mesothelioma / genetics
  • Mesothelioma / metabolism*
  • Mesothelioma / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Pemetrexed
  • Phosphorylation
  • Tumor Suppressor Protein p53 / biosynthesis*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • Glutamates
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Pemetrexed
  • Guanine
  • Caspases
  • Cisplatin