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

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 IC(50) values of approximately 5 μmol/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.

journal_name

Mol Cancer Ther

journal_title

Molecular cancer therapeutics

authors

Neher TM,Bodenmiller D,Fitch RW,Jalal SI,Turchi JJ

doi

10.1158/1535-7163.MCT-11-0303

subject

Has Abstract

pub_date

2011-10-01 00:00:00

pages

1796-806

issue

10

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-11-0303

journal_volume

10

pub_type

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