Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Thailand.
Breast Cancer Res Treat. 2011 Feb;126(1):203-9. doi: 10.1007/s10549-010-1182-7. Epub 2010 Sep 29.
The breast cancer susceptibility protein 1 (BRCA1) participates in the maintenance of cells genomic integrity through DNA repair, cell cycle checkpoint, protein ubiquitination, and transcriptional regulation. The N-terminus of BRCA1 contains a RING domain that preferentially forms a heterodimeric complex with BARD1. The BRCA1-BARD1 RING complex has an E3 ubiquitin ligase activity that plays an essential role in response to DNA damage. Preclinical and clinical studies have recently revealed that structural changes to the heterodimer result in alterations to the BRCA1-mediated DNA repair pathways in cancer cells, and lead to hypersensitivity to several chemotherapeutic agents. It is of interest to approach the BRCA1 RING domain as a potentially molecular target for platinum-based drugs for cancer therapy. A previous study has shown that the anticancer drug cisplatin formed intramolecular and intermolecular BRCA1 adducts in which His117 was the primary platinum-binding site, and conferred conformational changes and induced thermostability. Here, we have studied the functional consequence of the in vitro platination of the BRCA1 RING domain by a number of platinum complexes. The BRCA1 ubiquitin ligase activity was inhibited by transplatin > cisplatin > oxaliplatin > carboplatin in that order. The consequences of the binding of the platinum complexes on the reactivity of the BRCA1 were also discussed. The data raised the possibility of selectively targeting the BRCA1 DNA repair for cancer therapy.
乳腺癌易感蛋白 1（BRCA1）通过 DNA 修复、细胞周期检验点、蛋白质泛素化和转录调控参与维持细胞基因组的完整性。BRCA1 的 N 端含有一个 RING 结构域，该结构域优先与 BARD1 形成异二聚体复合物。BRCA1-BARD1 RING 复合物具有 E3 泛素连接酶活性，在应对 DNA 损伤中发挥着重要作用。最近的临床前和临床研究表明，异二聚体的结构变化导致癌细胞中 BRCA1 介导的 DNA 修复途径发生改变，并导致对几种化疗药物的敏感性增加。将 BRCA1 RING 结构域作为癌症治疗中铂类药物的潜在分子靶标进行研究是很有意义的。先前的一项研究表明，抗癌药物顺铂在体内形成了 BRCA1 内分子和外分子加合物，其中 His117 是主要的铂结合位点，并赋予构象变化和诱导热稳定性。在这里，我们研究了几种铂配合物体外铂化 BRCA1 RING 结构域的功能后果。BRCA1 泛素连接酶活性被反式顺铂>顺铂>奥沙利铂>卡铂按此顺序抑制。还讨论了铂配合物结合对 BRCA1 反应性的影响。这些数据提出了选择性针对 BRCA1 进行癌症治疗的可能性。
