Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl sulfonate ester

Cell Death Differ. 2001 Aug;8(8):817-28. doi: 10.1038/sj.cdd.4400863.


The poly(ADP-ribose) polymerase (PARP) is involved in cell recovery from DNA damage, such as methylation of N3-adenine, that activates the base excision repair process. In the present study we demonstrated that MeOSO(2)(CH(2))(2)-lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leukemic cell lines, depending on the presence of PARP inhibitor. Growth inhibition, provoked by the combination of Me-Lex and PARP inhibitor, was associated with a marked down-regulation of c-myc, increased generation of single strand breaks and apoptosis. When used as single agent, at concentrations that saturated cell repair ability, Me-Lex induced mainly cell death by necrosis. Surprisingly, addition of a PARP inhibitor enhanced apoptosis and reduced the early appearance of necrosis. Telomerase activity was completely suppressed in cells exposed to Me-Lex alone, by 24 h after treatment, whereas it did not change when Me-Lex was combined with PARP inhibitor. Thereafter, inhibition of telomerase was observed with both treatments. The results suggest new insights on different modalities of cell death induced by high levels of N3-methyladenine per se, or by the methylated base in the presence of PARP inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cell Division / drug effects
  • Cell Division / genetics
  • DNA Damage / drug effects*
  • DNA Damage / physiology
  • DNA Glycosylases*
  • DNA Methylation / drug effects*
  • DNA Repair / drug effects*
  • DNA Repair / physiology
  • DNA, Single-Stranded / drug effects
  • DNA, Single-Stranded / metabolism
  • DNA-Binding Proteins / drug effects*
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Humans
  • Jurkat Cells / cytology
  • Jurkat Cells / drug effects
  • Jurkat Cells / metabolism
  • N-Glycosyl Hydrolases / metabolism
  • Necrosis*
  • Netropsin / analogs & derivatives
  • Netropsin / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Proto-Oncogene Proteins c-myc / drug effects
  • Proto-Oncogene Proteins c-myc / genetics
  • Telomerase / drug effects
  • Telomerase / metabolism


  • Alkylating Agents
  • DNA, Single-Stranded
  • DNA-Binding Proteins
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • methyl lexitropsin
  • Netropsin
  • Poly(ADP-ribose) Polymerases
  • Telomerase
  • 3-methyladenine-DNA glycosylase
  • DNA Glycosylases
  • N-Glycosyl Hydrolases