A modified p53 enhances apoptosis in sarcoma cell lines mediated by doxorubicin

Br J Cancer. 2004 Mar 22;90(6):1285-92. doi: 10.1038/sj.bjc.6601653.


Mdm2 is frequently overexpressed in sarcoma cells and may contribute to drug resistance by increasing p53 degradation. We investigated the induction of apoptosis in sarcoma cells via adenovirus-mediated gene transfer of wild-type p53 and two modified p53 genes, p53 14/19 and p53 22/23, whose protein products are resistant to Mdm2-mediated degradation. We found that adenovirus-wt p53 (Ad-wt p53) induces significant apoptosis in HT1080 fibrosarcoma cells expressing low levels of Mdm2, but fails to induce apoptosis in SJSA osteosarcoma cells expressing high levels of Mdm2. In contrast, Ad-p53 14/19 induces significant apoptosis in both cell lines. Interestingly, Ad-p53 22/23, a vector encoding a transcription-defective p53 mutant, causes limited apoptosis in both cell lines. We demonstrate that doxorubicin induces phosphorylation of both wt p53 and p53 14/19 protein at multiple sites. We tested the efficacy of doxorubicin and cisplatin with either Ad-wt p53, Ad-p53 22/23 or Ad-p53 14/19. SJSA cells, although harbouring endogenous wt p53, did not undergo significant apoptosis following doxorubicin or cisplatin exposure alone or combined with Ad-wt p53. In contrast, doxorubicin or cisplatin plus Ad-p53 14/19 induced significant apoptosis. Gene transfer of p53 14/19 in combination with the administration of doxorubicin or cisplatin is a potential therapeutic approach for cancers expressing high levels of Mdm2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Antibiotics, Antineoplastic / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cisplatin / pharmacology*
  • Doxorubicin / pharmacology*
  • Gene Expression Regulation, Neoplastic
  • Gene Transfer Techniques
  • Genes, p53*
  • Genetic Vectors
  • Humans
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-mdm2
  • Sarcoma / genetics*
  • Sarcoma / pathology*
  • Tumor Cells, Cultured
  • Zinc Fingers


  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Doxorubicin
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Cisplatin