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[RuCl(-对异丙基苯)(,-双(二苯基膦基)-异丙胺)][BF]在乳腺癌模型中的筛选及初步生化与生物学研究

Screening and Preliminary Biochemical and Biological Studies of [RuCl(-cymene)(,-bis(diphenylphosphino)-isopropylamine)][BF] in Breast Cancer Models.

作者信息

Corrales Sánchez Veronica, Nieto-Jiménez Cristina, Castro-Osma José Antonio, de Andrés Fernando, Pacheco-Liñán Pedro J, Bravo Iván, Rodríguez Fariñas Nuria, Niza Enrique, Domínguez-Jurado Elena, Lara-Sánchez Agustín, Ríos Ángel, Gómez Juárez Mónica, Montero Juan Carlos, Pandiella Atanasio, Shafir Alexandr, Alonso-Moreno Carlos, Ocaña Alberto

机构信息

Oncología traslacional and CIBERONC, Unidad de Investigación del Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain.

Oncología traslacional, Centro Regional de Investigaciones Biomédicas, Dpto. Inorgánica, Orgánica y Bioquímica, Facultad de Farmacia de Albacete, Dpto. Química Analítica y Tecnología de Alimentos, Facultad de Farmacia de Albacete, Instituto Regional de Investigación Científica Aplicada IRICA, and Dpto. Química Física, Facultad de Farmacia de Albacete, UCLM, 02006 Albacete, Spain.

出版信息

ACS Omega. 2019 Aug 1;4(8):13005-13014. doi: 10.1021/acsomega.9b00296. eCollection 2019 Aug 20.

Abstract

Breast cancer is the second leading cause of cancer death worldwide. Despite progress in drug discovery, identification of the correct population is the limiting factor to develop new compounds in the clinical setting. Therefore, the aim of this study is to evaluate the effects of a new metallodrug, [RuCl(-cymene)(,-bis(diphenylphosphino)-isopropylamine)][BF] (), as a lead pnp-Ru compound by screening and preliminary biochemical and biological studies in different breast cancer subtypes. The results show that complex is much more effective in promoting in vitro cytotoxic effects on HER2+ and RH+/HER2- breast cancer than the reference metallodrugs cisplatin, carboplatin, or RAPTA-C. It is important to highlight that shows an impressive cytotoxicity against BT474 cells. Caspase-dependent apoptosis is the mechanism of action for these compounds. In addition, treatment of SKBR3, BT474, T47D, and MCF7 cancer cells with caused an accumulation of cells in the G0/G1 phase cells. The human serum albumin, DNA, and H1 histones binding properties of the lead compound are reported. Pharmacokinetic and biodistribution studies show a quick absorption of in serum with no significant accumulation in any of the tested organs. This work provides evidence to support the preclinical and clinical development of in breast cancer.

摘要

乳腺癌是全球癌症死亡的第二大主要原因。尽管在药物研发方面取得了进展,但确定正确的人群是在临床环境中开发新化合物的限制因素。因此,本研究的目的是通过在不同乳腺癌亚型中进行筛选以及初步的生化和生物学研究,评估一种新型金属药物[RuCl(-对异丙基苯)(,-双(二苯基膦基)-异丙胺)][BF] ()作为先导pnp-Ru化合物的效果。结果表明,与参考金属药物顺铂、卡铂或RAPTA-C相比,配合物对HER2+和RH+/HER2-乳腺癌的体外细胞毒性作用更有效。值得注意的是,对BT474细胞显示出令人印象深刻的细胞毒性。半胱天冬酶依赖性凋亡是这些化合物的作用机制。此外,用处理SKBR3、BT474、T47D和MCF7癌细胞会导致细胞在G0/G1期积累。报告了先导化合物与人血清白蛋白、DNA和H1组蛋白的结合特性。药代动力学和生物分布研究表明,在血清中吸收迅速,在任何测试器官中均无明显蓄积。这项工作为支持在乳腺癌中的临床前和临床开发提供了证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/062b/6704442/fda5f65ab7a2/ao-2019-002964_0001.jpg

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