Huang Fei, Mazin Alexander V
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2014 Jun 27;9(6):e100993. doi: 10.1371/journal.pone.0100993. eCollection 2014.
The homologous recombination pathway is responsible for the repair of DNA double strand breaks. RAD51, a key homologous recombination protein, promotes the search for homology and DNA strand exchange between homologous DNA molecules. RAD51 is overexpressed in a variety of cancer cells. Downregulation of RAD51 by siRNA increases radio- or chemo-sensitivity of cancer cells. We recently developed a specific RAD51 small molecule inhibitor, B02, which inhibits DNA strand exchange activity of RAD51 in vitro. In this study, we used human breast cancer cells MDA-MB-231 to investigate the ability of B02 to inhibit RAD51 and to potentiate an anti-cancer effect of chemotherapeutic agents including doxorubicin, etoposide, topotecan, and cisplatin. We found that the combination of B02 with cisplatin has the strongest killing effect on the cancer cells. We then tested the effect of B02 and cisplatin on the MDA-MB-231 cell proliferation in mouse xenografts. Our results showed that B02 significantly enhances the therapeutic effect of cisplatin on tumor cells in vivo. Our current data demonstrate that use of RAD51-specific small molecule inhibitor represents a feasible strategy of a combination anti-cancer therapy.
同源重组途径负责修复DNA双链断裂。RAD51是一种关键的同源重组蛋白，可促进同源性搜索以及同源DNA分子之间的DNA链交换。RAD51在多种癌细胞中过表达。通过siRNA下调RAD51可增加癌细胞的放射敏感性或化学敏感性。我们最近开发了一种特异性的RAD51小分子抑制剂B02，它在体外可抑制RAD51的DNA链交换活性。在本研究中，我们使用人乳腺癌细胞MDA-MB-231来研究B02抑制RAD51的能力以及增强包括阿霉素、依托泊苷、拓扑替康和顺铂在内的化疗药物的抗癌效果。我们发现B02与顺铂联合使用对癌细胞的杀伤作用最强。然后我们测试了B02和顺铂对MDA-MB-231细胞在小鼠异种移植瘤中增殖的影响。我们的结果表明，B02可显著增强顺铂在体内对肿瘤细胞的治疗效果。我们目前的数据表明，使用RAD51特异性小分子抑制剂是一种可行的联合抗癌治疗策略。
