Investigation of the Effects and Mechanisms of Anticancer Action of a Ru(II)‐Arene Iminophosphorane Compound in Triple Negative Breast Cancer Cells

Abstract

Dedicated to Prof. Adoración Gómez-Quiroga, cancer survivor and outstanding medicinal inorganic chemist.Triple negative breast cancer (TNBC) is one of the breast cancers with poorer prognosis and survival rates. TNBC has a disproportionally high incidence and mortality in women of African descent. We report on the evaluation of Ru-IM (1), a watersoluble organometallic ruthenium compound, in TNBC cell lines derived from patients of European (MDA-MB-231) and African (HCC-1806) ancestry (including IC 50 values, cellular and organelle uptake, cell death pathways, cell cycle, effects on migration, invasion, and angiogenesis, a preliminary proteomic analysis, and an NCI 60 cell-line panel screen). 1 was previously found highly efficacious in MDA-MB-231 cells and xenografts, with little systemic toxicity and preferential accumulation in the tumor. We observe a similar profile for this compound in the two cell lines studied, which includes high cytotoxicity, apoptotic behavior and potential antimetastatic and antiangiogenic properties. Cytokine M-CSF, involved in the PI3/AKT pathway, shows protein expression inhibition with exposure to 1. We also demonstrate a p53 independent mechanism of action.

Intracellular Localization Studies of the Luminescent Analogue of an Anticancer Ruthenium Iminophosphorane with High Efficacy in a Triple-Negative Breast Cancer Mouse Model

“…25-fold less toxic than 1, while 3b is 43-fold less toxic. Compounds 3b and especially 1 are less toxic to noncancerous lung fibroblasts but are toxic to nonmalignant breast cancer cell lines MCF10a (an effect that we 26 and others 44 have also observed for a variety of metal-based compounds in this cell line, including compounds like 1, which have low or no systemic toxicity in vivo in mice models).…”

“…62 For most anticancer drugs that generate ROS and provoke apoptosis, there is an activation of intrinsic pathways that involves an increase of the mitochondrial permeability, the release of activator factors, and the activation of caspases. 58 We have demonstrated that 1 exerts canonical or caspasedependent apoptosis, 23,24,26 which is in accordance with the results described here (accumulation in the mitochondria and generation of ROS).…”

“…12 h. 23,24 More recently, we have reported on the evaluation of this compound in a panel of TNBC cancer cell lines from different ethnic backgrounds, as well as against the National Cancer Institute (NCI) 60-cell-line panel. 26 Compound 1 was highly cytotoxic against most cancer types and cell lines. In addition, we reported that 1 induces apoptosis (G2/M arrest) and displays potential antimetastatic and antiangiogenic properties in two TNBC cell lines (MDA-MB-231 and HCC-1806) that are derived from patients with European and African ancestry, respectively.…”

“…Preliminary proteomic assays point to a potential involvement of the PI3K/AKT pathway. 26 Fluorophores based on the BODIPY core (4,4-difluoro-4bora-3a,4a-diaza-s-indacene) are attractive dyes utilized for diverse applications including biomolecular labeling. These dyes have features that make them particularly appealing for this application, such as photochemical and chemical stability and high absorption coefficients and quantum yields.…”

“…More recently, we have reported on the evaluation of this compound in a panel of TNBC cancer cell lines from different ethnic backgrounds, as well as against the National Cancer Institute (NCI) 60-cell-line panel . Compound 1 was highly cytotoxic against most cancer types and cell lines.…”