Resistance to radiation-induced apoptosis in Bcl-2-expressing cells is reversed by depleting cellular thiols

Oncogene. 1997 Sep 18;15(12):1461-70. doi: 10.1038/sj.onc.1201310.


The mechanism by which Bcl-2 oncogene expression inhibits radiation-induced apoptosis has been investigated in two mouse lymphoma cell lines: line LY-as is radiation sensitive, displays substantial radiaton-induced apoptosis, and expresses low levels of Bcl-2; line LY-ar is radiation-resistant, displays a low apoptosis propensity, and expresses 30-fold higher amount of Bcl-2 protein than does the sensitive line. We observed that upon incubation in cystine/methionine-free (C/M-) medium, radiation-induced apoptosis in the LY-ar cells was restored to levels comparable to that seen in the LY-as cells. lntracellular glutathione (GSH) concentrations in LY-ar cells incubated in C/M- medium plummeted to 50% of control values within 2 h. LY-ar cells treated with diethyl maleate (DEM) or diamide, agents that deplete cellular thiols, had increased susceptibility to radiation-induced apoptosis in a manner similar to C/M- medium. These results are consistent with the general idea that Bcl-2 expression blocks apoptosis through an antioxidant pathway that involves cellular thiols. That Bcl-2-expressing tumor cells can be sensitized by exogeneous agents that modify cellular thiols offers strategies for overcoming such resistance.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis / radiation effects
  • Buthionine Sulfoximine / pharmacology
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • DNA Fragmentation
  • Dose-Response Relationship, Radiation
  • Genes, bcl-2*
  • Glutathione / metabolism
  • Kinetics
  • Lymphoma
  • Mice
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Radiation Tolerance*
  • Time Factors
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / biosynthesis
  • bcl-2-Associated X Protein


  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • Buthionine Sulfoximine
  • Glutathione