Screening and preliminary biochemical and biological studies of [RuCl(p-cymene)(N, N-bis(diphenylphosphino)-isopropylamine)][BF4] in Breast Cancer Models

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. Copyright © 2019 American Chemical Society.The authors gratefully acknowledge financial support from the Ministerio de Economı́a y Competitividad (MINECO), Spain (grant nos. CTQ2017-84131-R, CTQ2016-81797-REDC) 350 Programa Redes Consolider CTQ2016-78793-P, CTQ2017-86936-P, the Instituto de Salud Carlos III (PI16/01121), ACEPAIN, Diputación de Albacete, CIBERONC, and CRIS Cancer Foundation (to A.O.) and JJCC Castilla-La Mancha (grant no. SBPLY/17/180501/000262), as well as AGAUR (Gen. Catalunya, 2017 SGR 1051). ED thanks AECC for financial support.Peer reviewe