N-methylpurine DNA glycosylase and DNA polymerase β modulate BER inhibitor potentiation of glioma cells to temozolomide

Jiang Bo Tang, David Svilar, Ram N. Trivedi, Xiao Hong Wang, Eva M. Goellner, Briana Moore, Ronald L. Hamilton, Lauren A. Banze, Ashley R. Brown, Robert W. Sobol

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

Temozolomide (TMZ) is the preferred chemotherapeutic agent in the treatment of glioma following surgical resection and/or radiation. Resistance to TMZ is attributed to efficient repair and/or tolerance of TMZ-induced DNA lesions. The majority of the TMZ-induced DNA base adducts are repaired by the base excision repair (BER) pathway and therefore modulation of this pathway can enhance drug sensitivity. N-methylpurine DNA glycosylase (MPG) initiates BER by removing TMZ-induced N3-methyladenine and N7-methylguanine base lesions, leaving abasic sites (AP sites) in DNA for further processing by BER. Using the human glioma cell lines LN428 and T98G, we report here that potentiation of TMZ via BER inhibition [methoxyamine (MX), the PARP inhibitors PJ34 and ABT-888 or depletion (knockdown) of PARG] is greatly enhanced by over-expression of the BER initiating enzyme MPG. We also show that methoxyamine-induced potentiation of TMZ in MPG expressing glioma cells is abrogated by elevated-expression of the rate-limiting BER enzyme DNA polymerase β (Polβ), suggesting that cells proficient for BER readily repair AP sites in the presence of MX. Further, depletion of Polβ increases PARP inhibitor-induced potentiation in the MPG over-expressing glioma cells, suggesting that expression of Polβ modulates the cytotoxic effect of combining increased repair initiation and BER inhibition. This study demonstrates that MPG overexpression, together with inhibition of BER, sensitizes glioma cells to the alkylating agent TMZ in a Polβ-dependent manner, suggesting that the expression level of both MPG and Polβ might be used to predict the effectiveness of MX and PARP-mediated potentiation of TMZ in cancer treatment.

Original languageEnglish
Pages (from-to)471-486
Number of pages16
JournalNeuro-Oncology
Volume13
Issue number5
DOIs
StatePublished - May 2011

Keywords

  • Base excision repair
  • Methoxyamine
  • N-methylpurine DNA glycosylase
  • Poly(ADP-ribose) polymerase
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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