Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA methyltransferase activity

Mol Cancer Ther. 2009 Aug;8(8):2232-42. doi: 10.1158/1535-7163.MCT-09-0142. Epub 2009 Aug 11.


The poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 potentiates the antitumor activity of temozolomide (TMZ). TMZ resistance results from increased O(6)-methylguanine-DNA methyltransferase (MGMT) activity and from mismatch repair (MMR) system mutations. We evaluated the relative importance of MGMT activity, MMR deficiency, nonhomologous end joining (NHEJ), and PARP activity in ABT-888 potentiation of TMZ. MMR-proficient and MMR-deficient leukemia cells with varying MGMT activity, as well as primary leukemia samples, were used to determine TMZ IC(50) alone and with ABT-888. ABT-888 effectively inhibited PARP activity and enhanced TMZ growth inhibition in most leukemia cells. ABT-888 potentiation was most effective in MMR-deficient cells with low MGMT activity [potentiation factor (PF) = 21]. ABT-888 also potentiated TMZ activity in MMR-deficient cells with elevated MGMT activity. Unexpectedly, ABT-888 also enhanced TMZ activity in MMR-proficient cells (PF = 3-7). ABT-888 potentiation was unrelated to NHEJ activity. ABT-888 potentiated TMZ (PF = 2-5) in two of four acute myeloid leukemia patient samples but showed little potentiation in primary acute lymphoblastic leukemia. In conclusion, although ABT-888 potentiation of TMZ was most pronounced in MMR-deficient cells with low MGMT activity, neither MMR proficiency nor MGMT overexpression completely abrogated ABT-888 potentiation of TMZ.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / toxicity*
  • Benzimidazoles / pharmacology*
  • Cell Line, Tumor
  • DNA Mismatch Repair
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / toxicity
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Leukemia / drug therapy*
  • Leukemia / enzymology
  • O(6)-Methylguanine-DNA Methyltransferase / genetics
  • O(6)-Methylguanine-DNA Methyltransferase / metabolism*
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Temozolomide


  • Antineoplastic Agents, Alkylating
  • Benzimidazoles
  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • veliparib
  • Dacarbazine
  • O(6)-Methylguanine-DNA Methyltransferase
  • Temozolomide