Structural basis and anticancer properties of ruthenium-based drug complexed with human serum albumin

• Published in: European journal of medicinal chemistry 2014-10, Vol.86, p.449-455
• Main Authors: Zhang, Yao, Ho, Andy, Yue, Jiping, Kong, Linlin, Zhou, Zuping, Wu, Xiaoyang, Yang, Feng, Liang, Hong
• Format: Article
• Language: English
• Subjects: Anticancer activity; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle - drug effects; Cell Line; Cell Proliferation - drug effects; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug delivery systems; Drug Screening Assays, Antitumor; Human serum albumin; Humans; Interactions of protein–ligand; Models, Molecular; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Ruthenium - chemistry; Ruthenium-based drugs; Serum Albumin - chemistry; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.08.071

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. HSA–Ru drugs complex selectively accumulating in cancer cells by enhanced permeability and retention effect, which improves drugs' targeting and efficiency to some extent. [Display omitted] •RuCl5(ind) has two binding site in HSA.•RuCl5(ind) interacts with HSA by coordination bond.•HSA can improve targeting and efficiency of ruthenium drug to some extent.