Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells

J Med Chem. 2016 Apr 14;59(7):3003-17. doi: 10.1021/acs.jmedchem.5b01628. Epub 2016 Apr 1.

Abstract

Amifostine protects normal cells from DNA damage induction by ionizing radiation or chemotherapeutics, whereas cancer cells typically remain uninfluenced. While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quantification (based on γH2AX/53BP1 high-resolution immunofluorescence microscopy) that amifostine treatment supports DSB repair in γ-irradiated normal NHDF fibroblasts but alters it in MCF7 carcinoma cells. These effects follow from the significantly lower activity of alkaline phosphatase measured in MCF7 cells and their supernatants as compared with NHDF fibroblasts. Liquid chromatography-mass spectrometry confirmed that the amifostine conversion to WR-1065 was significantly more intensive in normal NHDF cells than in tumor MCF cells. In conclusion, due to common differences between normal and cancer cells in their abilities to convert amifostine to its active metabolite WR-1065, amifostine may not only protect in multiple ways normal cells from radiation-induced DNA damage but also make cancer cells suffer from DSB repair alteration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / genetics
  • Alkaline Phosphatase / metabolism
  • Amifostine / pharmacokinetics
  • Amifostine / pharmacology*
  • Comet Assay
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Damage / drug effects*
  • DNA Repair / drug effects*
  • Fibroblasts / drug effects
  • Fibroblasts / radiation effects
  • Gamma Rays
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MCF-7 Cells / drug effects
  • MCF-7 Cells / radiation effects
  • Mercaptoethylamines / pharmacokinetics
  • Microscopy, Fluorescence / methods
  • Radiation-Protective Agents / pharmacology*
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • H2AX protein, human
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Mercaptoethylamines
  • Radiation-Protective Agents
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • N-(2-mercaptoethyl)-1,3-diaminopropane
  • Alkaline Phosphatase
  • Amifostine