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Amifostine impairs p53-mediated apoptosis of human myeloid leukemia cells

Juan C Acosta1, Carlos Richard, M Dolores Delgado

  • 1Grupo de Biología Molecular del Cáncer, Departamento de Biologia Molecular, Unidad de Biomedicina-CSIC, Universidad de Cantabria, Santander, Spain.

Molecular Cancer Therapeutics
|October 14, 2003
PubMed

Insights

Amifostine reduces p53-mediated apoptosis in myeloid leukemia cells by inhibiting the activation of key genes. This cytoprotective effect may decrease the efficacy of certain cancer treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Amifostine is a cytoprotective agent used in cancer therapy.
  • It has shown to protect against apoptosis and stimulate hematopoiesis.
  • p53-mediated apoptosis is a common pathway for anti-tumor agents.

Purpose of the Study:

  • To investigate the effect of amifostine on p53-mediated apoptosis in human myeloid leukemia cells.
  • To elucidate the molecular mechanisms underlying amifostine's impact on p53 activity.

Main Methods:

  • Utilized human myeloid leukemia cell lines (K562 and NB4) with temperature-conditional p53.
  • Assessed apoptosis using cell morphology, annexin V binding, sub-G1 cell fraction, and DNA laddering.
  • Analyzed p53 transcriptional activity and mRNA levels of p53 target genes via macroarray analysis.

Main Results:

  • Amifostine significantly reduced p53-induced apoptosis in both cell lines.
  • Amifostine decreased p53-mediated transactivation of target promoters.
  • Down-regulation of p53 target genes (p21(Waf1), mdm2, gadd45, pig8, pig3) and up-regulation of c-myc were observed.

Conclusions:

  • Amifostine impairs p53-dependent apoptosis in myeloid leukemia cells by suppressing apoptosis-related gene activation.
  • This mechanism suggests amifostine might reduce the effectiveness of p53-dependent anti-cancer therapies.

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