The trans -[Ru(PPh 3 ) 2 ( N , N -dimethyl- N ′-thiophenylthioureato-k 2 O,S)(bipy)]PF 6 complex has pro-apoptotic effects on triple negative breast cancer cells and presents low toxicity in vivo

Abstract

Triple negative breast cancer (TNBC) is a heterogeneous subtype of breast tumors that does not exhibit the expression of estrogen and progesterone receptors, neither the amplification of the human epidermal growth factor receptor 2 (HER-2) gene. Despite all the advances in cancer treatments, the development of new anticancer drugs for TNBC tumors is still a challenge. There is an increasing interest in new agents to be used in cancer treatment. Ruthenium is a metal that has unique characteristics and important in vivo and in vitro results achieved for cancer treatment. Thus, in this work, with the aim to develop anticancer drugs, three new ruthenium complexes containing acylthiourea ligands have been synthesized and characterized: trans-[Ru(PPh)(N,N-dibutyl-N'-benzoylthioureato-kO,S)(2,2'-bipyridine (bipy))]PF(1), trans-[Ru(PPh)(N,N-dimethyl-N'-thiophenylthioureato-kO,S)(bipy)]PF(2) and trans-[Ru(PPh)(N,N-dimethyl-N'-benzoylthioureato-kO,S)(bipy)]PF(3). Then, the cytotoxicity of these three new ruthenium complexes was investigated in TNBC MDA-MB-231 and in non-tumor MCF-10A cells. Complex (2) was the most selective complex and was chosen for further studies to verify its effects on cell morphology, adhesion, migration, invasion, induction of apoptosis and DNA damage in vitro, as well as its toxicity and capacity of causing DNA damage in vivo. Complex (2) inhibited proliferation, migration, invasion, adhesion, changed morphology and induced apoptosis, DNA damage and nuclear fragmentation of TNBC cells at lower concentrations compared to non-tumor MCF-10A cells, suggesting an effective action for this complex on tumor cells. Finally, complex (2) did not induce toxicity or caused DNA damage in vivo when low doses were administered to mice.

Rationally Designed Ruthenium Complexes for Breast Cancer Therapy

“…The in vivo toxicity of (30) was assessed using a mice model. At the doses administered intraperitoneally (50 and 300 mg/kg), this compound did not lead to a change in the weight of the animal compared to the control groups, which is indicative of a low toxicity [129].…”

“…Cominetti et al (2018) also reported a ruthenium(II) complex of acylthiourea, (30) ( Figure 10), which was also found to be active against TNBC tumor cells [129]. The inhibition of proliferation, migration, invasion, and adhesion was observed for cancer cells exposed to (30).…”

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.…”

“…However, available evidence suggests that their action could be mediated by the inhibition of matrix metalloproteinases (MMPs) [59], enzymes with the ability to degrade extracellular matrix proteins, after interaction with the αvβ3 integrin receptor [62]. Likewise, it has been suggested that NPMBC could inhibit epithelial-mesenchymal transition [65] and modify the structure of the actin cytoskeleton, interfering with the function of integrins [58,59] and under-regulating the phosphorylation of the focal adhesion kinase (FAK) [51]. No less important are the studies which highlight their role in inflammation [89,90].…”

“…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,…”