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

Screening and Preliminary Biochemical and Biological Studies of [RuCl(p-cymene)(N,N-bis(diphenylphosphino)-isopropylamine)][BF4] in Breast Cancer Models.

Author information

1
Oncología traslacional and CIBERONC, Unidad de Investigación del Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain.
2
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.
3
Dpto. Química Analítica, Facultad de Ciencias Ambientales y Bioquímicas de Toledo, UCLM, 45071 Toledo, Spain.
4
Dpto. Química Analítica y Tecnología de Alimentos, Facultad de Ciencias y Tecnologías Químicas de Ciudad Real, UCLM, 13005 Ciudad Real, Spain.
5
Centro de Investigación del Cáncer-CSIC, IBSAL-Salamanca and CIBERONC, 37007 Salmanca, Spain.
6
Department of Biological Chemistry, Institute of Advanced Chemistry of Catalonia, IQAC-CSIC, c/Jordi Girona 18-26, 08034 Barcelona, Spain.
7
Hospital Clinico San Carlos, 28040 Madrid, Spain.

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(p-cymene)(N,N-bis(diphenylphosphino)-isopropylamine)][BF4] (pnpRu-14), as a lead pnp-Ru compound by screening and preliminary biochemical and biological studies in different breast cancer subtypes. The results show that complex pnpRu-14 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 pnpRu-14 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 pnpRu-14 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 pnpRu-14 in serum with no significant accumulation in any of the tested organs. This work provides evidence to support the preclinical and clinical development of pnpRu-14 in breast cancer.

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