Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action

Abstract

Looking for new metal-based anticancer treatments, in recent years many ruthenium complexes have been proposed as effective and safe potential drugs. In this context we have recently developed a novel approach for the in vivo delivery of Ru(III) complexes, preparing stable ruthenium-based nucleolipidic nanoaggregates endowed with significant antiproliferative activity. Herein we describe the cellular response to our ruthenium-containing formulations in selected models of human breast cancer. By in vitro bioscreens in the context of preclinical studies, we have focused on their ability to inhibit breast cancer cell proliferation by the activation of the intrinsic apoptotic pathway, possibly via mitochondrial perturbations involving Bcl-2 family members and predisposing to programmed cell death. In addition, the most efficient ruthenium-containing cationic nanoaggregates we have hitherto developed are able to elicit both extrinsic and intrinsic apoptosis, as well as autophagy. To limit chemoresistance and counteract uncontrolled proliferation, multiple cell death pathways activation by metal-based chemotherapeutics is a challenging, yet very promising strategy for targeted therapy development in aggressive cancer diseases, such as triple-negative breast cancer with limited treatment options. These outcomes provide valuable, original knowledge on ruthenium-based candidate drugs and new insights for future optimized cancer treatment protocols.

Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity

“…In order to verify the antiproliferative efficacy of the nucleolipid-or aminoacyl lipid-based Ru(III) complexes inserted in POPC-and DOTAP-based formulations, detailed investigations on their in vitro bioactivity were performed in comparison with naked AziRu [77,79,100,[105][106][107]110,134]. A selected panel of human and non-human cancer cell lines was chosen, particularly focusing on cells of different histopathological origin and widely used in anticancer research due to their replicative potential and malignancy, such as MCF-7 (human breast adenocarcinoma cell line), WiDr (human epithelial colorectal adenocarcinoma cell line), HeLa (human cervical cancer cells) and C6 (tumour rat glioma cells) [134][135][136]. In parallel experiments, some of these formulations were also tested on normal cell lines, such as L6 (rat muscle cells) and HaCaT (human keratinocytes cells), representing useful models to assess possible biological effect on healthy cells [137].…”

Non-Platinum Metal Complexes as Potential Anti-Triple Negative Breast Cancer Agents

“…NPMBC inhibit the growth of TNBC cells better than non-TNBC cells [66]. Furthermore, NPMBC of which effects are dose- [49,53,55,67] and time- [63,67] dependent could be more cytotoxic than platinum-based drugs [52,53,57,58,68]. For example, Biancalana et al [57] observed that ruthenium complexes have good cytotoxic activity, with IC 50 values substantially lower than the values obtained with cisplatin on MDA-MB-231 cells.…”

“…Furthermore, a study suggests that NPMBC could also inhibit angiogenesis [55]; however, because of scarce evidence, no definitive conclusion can be drawn on the role of these compounds in the regulation of blood vessel formation. In any case, it is thought that NPMBC are frequently multi-targeted and attack different biochemical pathways simultaneously [53,66,68], sometimes in a synergic way [37,62]. Cellular studies constitute an important step in the development of drugs; however, demonstrating efficacy in suitable animal models and validating cellular observations in vivo are a condition sine qua non for clinical trials investigating potential anticancer agents.…”

“…However, both cisplatin chemotherapies and its analogs have been shown to have major drawbacks (i.e., intrinsic and acquired chemoresistance, high general toxicity and limited spectrum of activity) [26] which have motivated extensive investigations into alternative metal-based cancer therapies that effectively target both cancer cell proliferation and metastasis. In this sense, we can mention chemotherapy with gold compounds [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]-because they are nontoxic, nonimmunogenic and have good photothermal and optical properties, biocompatibility and stability [40,47,48]-and also with copper [49][50][51], ruthenium [16,[52][53][54][55][56][57][58][59], iron [56,[60][61][62][63][64][65], palladium [50], silver [66,…”

Induction of Hair Keratins Expression by an Annurca Apple-Based Nutraceutical Formulation in Human Follicular Cells

“…If trypan blue is detected, the instrument also accounts for the dilution and shows live cell count and percent viability. Total counts and live/dead ratio from random samples for each cell line were subjected to comparisons with manual hemocytometers in control experiments [29].…”