Amifostine impairs p53-mediated apoptosis of human myeloid leukemia cells

Juan C Acosta, Carlos Richard, M Dolores Delgado, Machiko Horita, M Giulia Rizzo, Jose L Fernández-Luna, Javier León

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Amifostine is used as a cytoprotective agent in cancer treatments. Amifostine protects from apoptosis in some models and has been used as hematopoiesis stimulator in myeloid malignancies. As the apoptosis induced by many antitumoral agents is mediated by p53, we studied the effect of amifostine on p53-mediated apoptosis. We used human myeloid leukemia K562 and NB4 cells expressing the temperature-conditional p53-Val(135) mutant. Both cell lines undergo apoptosis at 32 degrees C due to the presence of p53 in wild-type conformation. We found that amifostine dramatically reduced apoptosis by p53 in both cell lines, as assessed by cell morphology, annexin V binding, fraction of sub-G(1) cells, and DNA laddering. To explore the mechanism responsible for this apoptosis protection, we tested the effect of amifostine on p53 transcriptional activity. We found that amifostine reduced p53-mediated transactivation of target promoters in NB4 and K562. Macroarray analysis confirmed that several p53 target genes as p21(Waf1), mdm2, gadd45, pig8, and pig3 were down-regulated at the mRNA level by amifostine in NB4 and K562. Also, c-myc was up-regulated by amifostine in K562 in the presence of p53, consistently with the impairment of p53-mediated apoptosis exerted by c-Myc in these cells. We conclude that amifostine impairs p53-dependent apoptosis of myeloid leukemia cells by reducing the activation of apoptosis-related genes. Our results open the possibility that amifostine could reduce the effectiveness of antitumoral treatments when it is dependent on active p53.
Original languageEnglish
Pages (from-to)893-900
Number of pages8
JournalMolecular Cancer Therapeutics
Issue number9
Publication statusPublished - Sept 2003

Keywords / Materials (for Non-textual outputs)

  • Immunoblotting
  • Radiation-Protective Agents
  • Tumor Suppressor Protein p53
  • Apoptosis
  • Blotting, Northern
  • Oligonucleotide Array Sequence Analysis
  • Amifostine
  • Humans
  • Annexin A5
  • Leukemia, Myeloid
  • Caspases
  • Gene Expression Regulation, Leukemic
  • bcl-X Protein
  • Transcriptional Activation
  • Proto-Oncogene Proteins c-bcl-2
  • Gene Expression Profiling
  • Neoplasm Proteins
  • Tumor Cells, Cultured
  • Luciferases
  • Fluorescent Antibody Technique
  • Protein Transport


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