Novel irreversible small molecule inhibitors of replication protein A display single-agent activity and synergize with cisplatin.
Novel irreversible small molecule inhibitors of replication protein A display single-agent activity and synergize with cisplatin.
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DOI：
10.1158/1535-7163.mct-11-0303
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发表时间：
2011-10
影响因子：
5.7
通讯作者：
Turchi JJ
中科院分区：
文献类型：
--
作者：
Neher TM;Bodenmiller D;Fitch RW;Jalal SI;Turchi JJ
Replication protein A (RPA) is a single-strand DNA-binding protein with essential roles in DNA replication, recombination and repair. RPA is necessary for the formation of the preincision complex which is required for proper incision of damaged DNA nucleotides during DNA repair. We have previously identified small molecule inhibitors (SMIs) with the ability to disrupt RPA binding activity to ssDNA. Further characterization of these RPA inhibitors was assessed using both lung and ovarian cancer cell lines. Lung cancer cell lines demonstrated increased apoptotic cell death following treatment with the SMI MCI13E, with IC50 values of ~5 μM. The A2780 ovarian cancer cell line and the p53-null lung cancer cell line H1299 were particularly sensitive to MCI13E treatment with IC50 values below 3 μM. Furthermore, a cell cycle effect was observed in lung cancer cell lines which resulted in a lengthening of either G1 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 RPA’s DNA binding activity via a SMI may disrupt RPA’s role in cell cycle regulation. Thus, RPA SMIs hold the potential to be used as single agent chemotherapeutics or in combination with current chemotherapeutic regimens to increase efficacy.
