亚硝基钌复合物的细胞毒性和抗增殖特性及其对 HepG2 细胞系细胞色素 P450 的调节作用。

Q3 Biochemistry, Genetics and Molecular Biology
L S Klyushova, V A Vavilin, A Yu Grishanova
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引用次数: 0

摘要

亚硝基钌复合物作为抗肿瘤药物正受到积极研究。在早期药物开发过程中,会定期评估细胞色素 P450(CYPs)与新化合物之间的潜在相互作用。在本研究中,我们研究了钌亚硝基复合物与烟酸和异烟酸的甲酯/乙酯以及γ-甲基吡啶对二维和三维培养的人肝癌 HepG2 和非癌症人肺成纤维细胞 MRC-5 的细胞毒性和抗增殖活性,评估了它们在 λrad = 445 纳米波长下的光诱导活性,还评估了它们对 CYP3A4、CYP2C9 和 CYP2C19 的调节作用。采用基于表型的高含量筛选(HCS)方法研究了这些药物对二维和三维细胞模型的细胞毒性和抗增殖活性。利用基于靶点的高内涵筛选(HCS)研究了 CYP3A4、CYP2C9 和 CYP2C19 mRNA 及 CYP3A4 蛋白的表达。实时反转录聚合酶链反应(RT-PCR)证实了 CYP3A4 mRNA 的表达结果。亚硝基钌复合物对 HepG2 和 MRC-5 细胞具有剂量依赖性的细胞毒性作用。与异烟酸乙酯(1)和烟酸(3、4)的复合物对 MRC-5 细胞的细胞毒活性明显低于对 HepG2 细胞的细胞毒活性;与异烟酸甲酯(2)的复合物对 MRC-5 细胞的细胞毒活性高于对 HepG2 细胞的细胞毒活性;与γ-吡啶(5)的复合物对两种细胞系的细胞毒活性相当。复合物 2 和 5 对 MRC-5 的抗增殖作用高出一个数量级;复合物 1、3 和 4 对两种细胞系的抗增殖作用相当。除 4 外,所有复合物对 3D HepG2 的细胞毒活性都低于对 2D HepG2 的细胞毒活性。其细胞毒性活性降低,而抗增殖活性提高。亚硝基钌复合物 1-4 是 CYP3A4 和 CYP2C19 的诱导剂,而与γ-吡啶的复合物(5)则诱导 CYP3A4。在所研究的亚硝基钌配合物中,最有潜力的抗肿瘤化合物是与烟酸甲酯的钌配合物(4)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The cytotoxic and antiproliferative properties of ruthenium nitrosyl complexes and their modulation effect on cytochrome P450 in the HepG2 cell line.

Ruthenium nitrosyl complexes are actively investigated as antitumor agents. Evaluation of potential interactions between cytochromes P450 (CYPs) with new compounds is carried out regularly during early drug development. In this study we have investigated the cytotoxic and antiproliferative activities of ruthenium nitrosyl complexes with methyl/ethyl esters of nicotinic and isonicotinic acids and γ-picoline against 2D and 3D cultures of human hepatocellular carcinoma HepG2 and non-cancer human lung fibroblasts MRC-5, assessed their photoinduced activity at λrad = 445 nm, and also evaluated their modulating effect on CYP3A4, CYP2C9, and CYP2C19. The study of cytotoxic and antiproliferative activities against 2D and 3D cell models was performed using phenotypic-based high content screening (HCS). The expression of CYP3A4, CYP2C9, and CYP2C19 mRNAs and CYP3A4 protein was examined using target-based HCS. The results of CYP3A4 mRNA expression were confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR). The ruthenium nitrosyl complexes exhibited a dose-dependent cytotoxic effect against HepG2 and MRC-5 cells. The cytotoxic activity of complexes with ethyl isonicotinate (1) and nicotinate (3, 4) was significantly lower for MRC-5 than for HepG2, for a complex with methyl isonicotinate (2) it was higher for MRC-5 than for HepG2, for a complex with γ-picoline (5) it was comparable for both lines. The antiproliferative effect of complexes 2 and 5 was one order of magnitude higher for MRC-5; for complexes 1, 3, and 4 it was comparable for both lines. The cytotoxic activity of all compounds for 3D HepG2 was lower than for 2D HepG2, with the exception of 4. Photoactivation affected the activity of complex 1 only. Its cytotoxic activity decreased, while the antiproliferative activity increased. The ruthenium nitrosyl complexes 1-4 acted as inducers of CYP3A4 and CYP2C19, while the complex with γ-picoline (5) induced of CYP3A4. Among the studied ruthenium nitrosyl complexes, the most promising potential antitumor compound is the ruthenium compound with methyl nicotinate (4).

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来源期刊
Biomeditsinskaya khimiya
Biomeditsinskaya khimiya Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
1.30
自引率
0.00%
发文量
49
期刊介绍: The aim of the Russian-language journal "Biomeditsinskaya Khimiya" (Biomedical Chemistry) is to introduce the latest results obtained by scientists from Russia and other Republics of the Former Soviet Union. The Journal will cover all major areas of Biomedical chemistry, including neurochemistry, clinical chemistry, molecular biology of pathological processes, gene therapy, development of new drugs and their biochemical pharmacology, introduction and advertisement of new (biochemical) methods into experimental and clinical medicine etc. The Journal also publish review articles. All issues of journal usually contain invited reviews. Papers written in Russian contain abstract (in English).
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