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

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)][BF 4 ] ( 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.

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

“…Anti-tumor effects when found in essential oils from Nigella sativa [295]. Ruthenium 11 (p-Cymene) complexes were effective and selective against several cancers [296][297][298].…”

“…p-Cymene is a common ligand for ruthenium, proposed as a potential alternative to platinum-based chemotherapies. Ruthenium II (p-Cymene) complexes have been suggested as effective and selective anticancer candidates under various forms for different cancer types [296][297][298].…”

Tuning the Cytotoxicity of Bis-Phosphino-Amines Ruthenium(II) Para-Cymene Complexes for Clinical Development in Breast Cancer

“…In a previous study, we reported Ru0 as the lead PNP-Ru compound by preliminary biochemical and biological studies in different breast cancer subtypes [37]. The results showed that complex Ru0 is much more effective in promoting in vitro cytotoxic effect on HER2+ and RH+/HER2− breast cancer cell lines than the reference metallodrugs cisplatin, carboplatin, or RAPTA-C [35].…”

“…On the basis of the cytotoxic results of Ru3 in breast cancer cell lines, the mechanism of cell death induction was evaluated. We analyzed Ru3 ability to induce apoptosis by flow cytometry as previously described [37,53,[55][56][57]. The experiments were performed using an incubation time of 48 h, and Ru3 concentrations corresponding to their respective IC 50 value.…”

“…In addition, the lead compound of the series was selected for further evaluation (Figure 1). In a second study, we focused our efforts on understanding its mode of action, pharmacokinetic and biodistribution parameters and proposed plausible targets to improve subsequent designs [37].…”