Novel irreversible small molecule inhibitors of replication protein A display single-agent activity and synergize with cisplatin

Tracy M. Neher, Diane Bodenmiller, Richard W. Fitch, Shadia Jalal, John Turchi

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Replication protein A (RPA) is a single-strand DNA-binding protein with essential roles in DNA replication, recombination, and repair. It is necessary for the formation of the preincision complex that is required for proper incision of damaged DNA nucleotides during DNA repair. We have previously identified small molecule inhibitors (SMI) with the ability to disrupt RPA-binding activity to ssDNA. Further characterization of these RPA inhibitors was done using both lung and ovarian cancer cell lines. Lung cancer cell lines showed increased apoptotic cell death following treatment with the SMI MCI13E, with IC50 values of approximately 5 mmol/L. The ovarian cancer cell line A2780 and the p53-null lung cancer cell line H1299 were particularly sensitive to MCI13E treatment, with IC 50 values less than 3 μmol/L. Furthermore, a cell-cycle effect was observed in lung cancer cell lines that resulted in a lengthening of either G 1 or S-phases of the cell cycle following single-agent treatment. Sequential treatment with MCI13E and cisplatin resulted in synergism. Overall, these data suggest that decreasing DNA-binding activity of RPA via a SMI may disrupt the role of RPA in cell-cycle regulation. Thus, SMIs of RPA hold the potential to be used as single-agent chemotherapeutics or in combination with current chemotherapeutic regimens to increase efficacy.

Original languageEnglish
Pages (from-to)1796-1806
Number of pages11
JournalMolecular Cancer Therapeutics
Volume10
Issue number10
DOIs
StatePublished - Oct 2011

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Replication Protein A
Cisplatin
Lung Neoplasms
Cell Line
Cell Cycle
DNA Repair
Ovarian Neoplasms
Recombinational DNA Repair
DNA
DNA-Binding Proteins
DNA Replication
S Phase
Protein Binding
Inhibitory Concentration 50
Cell Death
Nucleotides

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Novel irreversible small molecule inhibitors of replication protein A display single-agent activity and synergize with cisplatin. / Neher, Tracy M.; Bodenmiller, Diane; Fitch, Richard W.; Jalal, Shadia; Turchi, John.

In: Molecular Cancer Therapeutics, Vol. 10, No. 10, 10.2011, p. 1796-1806.

Research output: Contribution to journalArticle

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