Pifithrin-α as a Potential Cytoprotective Agent in Radiotherapy: Protection of Normal Tissue Without Decreasing Therapeutic Efficacy in Glioma Cells

Radiat Res. 2010 Nov;174(5):601-10. doi: 10.1667/RR2147.1. Epub 2010 Aug 18.

Abstract

Activation of p53 has been causally linked to normal tissue damage after irradiation. Pifithrin-α (PFT-α), a specific inhibitor of p53, has been suggested as a combinatory agent in the treatment of p53-deficient tumors in which inhibition of p53 would not compromise therapeutic efficacy but would decrease p53-mediated side effects in normal tissue. We tested this concept for radiotherapy of p53-deficient and -proficient glioma. We observed significant interaction of PFT-α with radiation-induced G(1) checkpoint activation and plating efficiency only in glioma cells expressing at least one wild-type allele of p53. This interaction was correlated with PFT-α-mediated inhibition of radiation-induced expression of the p53 target gene p21(Waf1). Despite inhibition of p53 function we did not observe significant changes in radiosensitivity after treatment with PFT-α in either p53-deficient or p53-proficient tumor cells. We confirmed these results in p53-proficient lung cancer cells. In contrast, PFT-α significantly increased the fraction of normal astrocytes and fibroblasts surviving irradiation; this was accompanied by improved DNA damage repair, speaking against an accumulation of cells with genetic lesions after PFT-α treatment. In conclusion, PFT-α might prove useful in protecting normal tissue from the side effects of radiotherapy without reducing the efficacy of treatment for both p53-proficient and -deficient tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / radiation effects
  • Benzothiazoles / pharmacology*
  • Cell Line, Tumor
  • Cytoprotection / drug effects*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / radiation effects
  • G1 Phase / drug effects
  • G1 Phase / radiation effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology*
  • Glioma / radiotherapy*
  • Humans
  • Radiation Injuries / pathology
  • Radiation Injuries / prevention & control
  • Radiation Tolerance / drug effects
  • Rats
  • Toluene / analogs & derivatives*
  • Toluene / pharmacology
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Benzothiazoles
  • Tumor Suppressor Protein p53
  • Toluene
  • pifithrin