Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Mol Cancer Ther. 2011 Oct;10(10):1796-806. doi: 10.1158/1535-7163.MCT-11-0303. Epub 2011 Aug 16.
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.
复制蛋白 A（RPA）是一种单链 DNA 结合蛋白，在 DNA 复制、重组和修复中具有重要作用。它是形成预切口复合物所必需的，该复合物是在 DNA 修复过程中正确切割受损 DNA 核苷酸所必需的。我们之前已经鉴定出具有破坏 RPA 与 ssDNA 结合活性的小分子抑制剂（SMI）。使用肺癌和卵巢癌细胞系进一步表征了这些 RPA 抑制剂。肺癌细胞系在用 SMI MCI13E 处理后显示出增加的凋亡细胞死亡，其 IC50 值约为 5 μmol/L。卵巢癌细胞系 A2780 和 p53 缺失的肺癌细胞系 H1299 对 MCI13E 治疗特别敏感，IC50 值小于 3 μmol/L。此外，在肺癌细胞系中观察到细胞周期效应，导致在单一药物处理后细胞周期的 G1 或 S 期延长。MCI13E 与顺铂的序贯治疗具有协同作用。总体而言，这些数据表明，通过 SMI 降低 RPA 的 DNA 结合活性可能会破坏 RPA 在细胞周期调控中的作用。因此，RPA 的 SMI 有可能单独用作化疗药物或与当前的化疗方案联合使用以提高疗效。
