Structural basis and anticancer properties of ruthenium-based drug complexed with human serum albumin.
Structural basis and anticancer properties of ruthenium-based drug complexed with human serum albumin.
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DOI：
10.1016/j.ejmech.2014.08.071
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发表时间：
2014-10
影响因子：
6.7
通讯作者：
Yao Zhang;A. Ho;J. Yue;Linlin Kong;Zuping Zhou;Xiaoyang Wu;Feng Yang;Hong Liang
中科院分区：
文献类型：
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作者：
Yao Zhang;A. Ho;J. Yue;Linlin Kong;Zuping Zhou;Xiaoyang Wu;Feng Yang;Hong Liang
在过去的二十年里，钌基抗癌配合物的研究越来越受欢迎。虽然钌配合物目前正在临床试验中进行研究，但其递送和相关副作用仍存在一些困难。基于人血清白蛋白（HSA）的递送系统有望提高抗癌药物的靶向性和减少副作用。然而，关于HSA作为金属基抗癌化合物载体的研究很少，也没有提及其结构机制。因此，我们研究了与HSA复合的基于钌的化合物[RuCl 5（ind）]2−的结构和抗癌性质。结构显示[RuCl 5（ind）]2−在HSA中有两个结合位点。在IB亚结构域中，[RuCl 5（ind）]2−通过与His-146配位结合到一个新的亚位点。在IIA亚结构域中，[RuCl 5（ind）]2−的钌（III）与疏水腔结合，并通过用HSA的His-242和Lys-199残基取代氯原子形成配位键。有趣的是，[RuCl 5（ind）]2−与HSA一起可以将癌细胞的细胞毒性提高2至5倍，但对体外正常细胞没有影响。与未结合的药物相比，HSA-[RuCl 5（ind）]2−复合物促进MGC-803细胞凋亡，并且在MGC-803中具有更强的将细胞周期阻滞在G2期的能力。总之，本研究将指导合理的设计和开发的药物，含或以药物为中心的药物和HSA传递系统的药物。
Ruthenium-based anticancer complexes have become increasingly popular for study over the last two decades. Although ruthenium complexes are currently being investigated in clinical trials, there are still some difficulties with their delivery and associated side effects. Human serum albumin (HSA)-based delivery systems are promising for improving anticancer drug targeting and reducing negative side effects. However, there have been few studies regarding the HSA delivery system for metal-based anticancer compounds and no mention of its structural mechanism. Therefore, we studied the structure and anticancer properties of the ruthenium-based compound [RuCl5(ind)]2−in complex with HSA. The structure revealed that [RuCl5(ind)]2−has two binding sites in HSA. In the IB subdomain, [RuCl5(ind)]2−binds to a new sub-site by coordinating with His-146. In the IIA subdomain, ruthenium (III) of [RuCl5(ind)]2−binds to the hydrophobic cavity and forms coordination bonds by replacing chlorine atoms with the His-242 and Lys-199 residues of HSA. Interestingly, [RuCl5(ind)]2−, together with HSA, can enhance cytotoxicity by two to five times in cancer cells but has no effect on normal cells in vitro. Compared with unbound drug, the HSA–[RuCl5(ind)]2−complex promotes MGC-803 cell apoptosis and also has a stronger capacity for cell cycle arrest at the G2 phase in MGC-803. In conclusion, this study will guide the rational design and development of ruthenium-containing or ruthenium-centered drugs and an HSA delivery system for ruthenium-based drugs.