A Novel inhibitor of DNA polymerase β enhances the ability of temozolomide to impair the growth of colon cancer cells

Aruna S. Jaiswal, Sanjeev Banerjee, Harekrushna Panda, Charles D. Bulkin, Tadahide Izumi, Fazlul H. Sarkar, David A. Ostrov, Satya Narayan

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

The recent emerging concept to sensitize cancer cells to DNA-alkylating drugs is by inhibiting various proteins in the base excision repair (BER) pathway. In the present study, we used structure-based molecular docking of DNA polymerase β (Pol-β) and identified a potent small molecular weight inhibitor, NSC-666715. We determined the specificity of this small molecular weight inhibitor for Pol-β by using in vitro activities of APE1, Fen1, DNA ligase I, and Pol-β-directed single-nucleotide and long-patch BER. The binding specificity of NSC-666715 with Pol-β was also determined by using fluorescence anisotropy. The effect of NSC-666715 on the cytotoxicity of the DNA-alkylating drug temozolomide (TMZ) to colon cancer cells was determined by in vitro clonogenic and in vivo xenograft assays. The reduction in tumor growth was higher in the combination treatment relative to untreated or monotherapy treatment. NSC-666715 showed a high specificity for blocking Pol-β activity. It blocked Pol-β-directed single-nucleotide and long-patch BER without affecting the activity of APE1, Fen1, and DNA ligase I. Fluorescence anisotropy data suggested that NSC-666715 directly and specifically interacts with Pol-β and interferes with binding to damaged DNA. NSC-666715 drastically induces the sensitivity of TMZ to colon cancer cells both in in vitro and in vivo assays. The results further suggest that the disruption of BER by NSC-666715 negates its contribution to drug resistance and bypasses other resistance factors, such as mismatch repair defects. Our findings provide the "proof-of-concept" for the development of highly specific and thus safer structure-based inhibitors for the prevention of tumor progression and/or treatment of colorectal cancer. (Mol Cancer Res 2009;7(12):1973-83)

Original languageEnglish (US)
Pages (from-to)1973-1983
Number of pages11
JournalMolecular Cancer Research
Volume7
Issue number12
DOIs
StatePublished - Dec 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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