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

ABSTRACT: 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 water-soluble organometallic ruthenium compound, in TNBC cell lines derived from patients of European (MDA-MB-231) and African (HCC-1806) ancestry (including IC₅₀ 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.

SUBMITTER: Nayeem N

PROVIDER: S-EPMC8571052 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Nayeem Nazia N Yeasmin Arefa A Cobos Samantha N SN Younes Ali A Hubbard Karen K Contel Maria M

ChemMedChem 20210824 21

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 water-soluble organometallic ruthenium compound, in TNBC cell lines derived from patients of European (MDA-MB-231) and African (HCC-1806) ancestry (including IC<sub>50</sub> values, cellular and organelle uptake, cell death pathways, cell cycle, effects on migr ...[more]

PMID: 34329530

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Project description:The potential of ruthenium(II) compounds as an alternative to platinum-based clinical anticancer agents has been unveiled after extensive research for over 2 decades. As opposed to cisplatin, ruthenium(II) compounds have distinct mechanisms of action that do not rely solely on interactions with DNA. In a previous report from our group, we described the synthesis, characterization, and biological evaluation of a cationic, water-soluble, organometallic ruthenium(II) iminophosphorane (IM) complex of p-cymene, ([(η6-p-cymene)Ru{(Ph3P═N-CO-2N-C5H4)-κ-N,O}Cl]Cl (1 or Ru-IM), that was found to be highly cytotoxic against a panel of cell lines resistant to cisplatin, including triple-negative breast cancer (TNBC) MDA-MB-231, through canonical or caspase-dependent apoptosis. Studies on a MDA-MB-231 xenograft mice model (after 28 days of treatment) afforded an excellent tumor reduction of 56%, with almost negligible systemic toxicity, and a favored ruthenium tumor accumulation compared to other organs. 1 is known to only interact weakly with DNA, but its intracellular distribution and ultimate targets remain unknown. To gain insight on potential mechanisms for this highly efficacious ruthenium compound, we have developed two luminescent analogues containing the BOPIPY fluorophore (or a modification) in the IM scaffold with the general structure of [(η6-p-cymene)Ru{(BODIPY-Ph2P═N-CO-2-NC5H4)-κ-N,O}Cl]Cl {BODIPY-Ph2P = 8-[(4-diphenylphosphino)phenyl]-4,4-dimethyl-1,3,5,7-tetramethyl-2,6-diethyl-4-bora-3a,4a-diaza-s-indacene (3a) and 4,4-difluoro-8-[4-[[2-[4-(diphenylphosphino)benzamido]ethyl]carbamoyl]phenyl]-1,3,5,7-tetramethyl,2,6-diethyl-4-bora-3a,4a-diaza-s-indacene (3b)}. We report on the synthesis, characterization, lipophilicity, stability, luminescence properties, and cell viability studies in the TNBC cell line MDA-MB-231, nonmalignant breast cells (MCF10a), and lung fibroblasts (IMR-90) of the new compounds. The ruthenium derivative 3b was studied by fluorescence confocal microscopy. These studies point to a preferential accumulation of the compound in the endoplasmic reticulum, mitochondria, and lysosomes. Inductively coupled plasma optical emission spectrometry (ICP-OES) analysis also confirms a greater ruthenium accumulation in the cytoplasmic fraction, including endoplasmic reticulum and lysosomes, and a smaller percentage of accumulation in mitochondria and the nucleus. ICP-OES analysis of the parent compound 1 indicates that it accumulates preferentially in the mitochondria and cytoplasm. Subsequent experiments in 1-treated MDA-MB-231 cells demonstrate significant reactive oxygen species generation.

Project description:Triple negative breast cancer (TNBC) is a breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression. TNBC cells respond poorly to targeted chemotherapies currently in use and the mortality rate of TNBC remains high. Therefore, it is necessary to identify new chemotherapeutic agents for TNBC. In this study, the anti-cancer effects of 7-α-hydroxyfrullanolide (7HF), derived from Grangea maderaspatana, on MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cells were assessed using MTT assay. The mode of action of 7HF in TNBC cells treated with 6, 12 and 24 µM of 7HF was determined by flow cytometry and propidium iodide (PI) staining for cell cycle analysis and annexin V/fluorescein isothiocyanate + PI staining for detecting apoptosis. The molecular mechanism of action of 7HF in TNBC cells was investigated by evaluating protein expression using proteomic techniques and western blotting. Subsequently, 7HF exhibited the strongest anti-TNBC activity toward MDA-MB-468 cells and a concomitantly weak toxicity toward normal breast cells. The molecular mechanism of action of low-dose 7HF in TNBC cells primarily involved G2/M-phase arrest through upregulation of the expression of Bub3, cyclin B1, phosphorylated Cdk1 (Tyr 15) and p53-independent p21. Contrastingly, the upregulation of PP2A-A subunit expression may have modulated the suppression of various cell survival proteins such as p-Akt (Ser 473), FoxO3a and β-catenin. The concurrent apoptotic effect of 7HF on the treated cells was mediated via both intrinsic and extrinsic modes through the upregulation of Bax and active cleaved caspase-7-9 expression and downregulation of Bcl-2 and full-length caspase-7-9 expression. Notably, the proteomic approach revealed the upregulation of the expression of pivotal protein clusters associated with G1/S-phase arrest, G2/M-phase transition and apoptosis. Thus, 7HF exhibits promising anti-TNBC activity and at a low dose, it modulates signal transduction associated with G2/M-phase arrest and apoptosis.

Project description:Triple-negative breast cancer (TNBC) is one of the most malignant cancers associated with early metastasis, poor clinical prognosis, and high recurrence rate. TNBC is a distinct subtype of breast cancer that lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptors (HER2). Development of effective TNBC therapies has been limited partially due to the lack of specific molecular targets and chemotherapy involving different cytotoxic drugs suffers from significant side effects and drug-resistance development. Therefore, there is an unmet need for the development of novel and efficient therapeutic drugs with reduced side effects to treat TNBC. We have previously reported that certain analogues of haloperidol (a typical antipsychotic drug used for treating mental/mood disorders such as schizophrenia and bipolar disorder) suppress the viability of a variety of solid tumor cell lines, and we have identified 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluoro-phenyl)butan-1-one (SYA013) with such antiproliferative properties. Interestingly, unlike haloperidol, SYA013 shows moderate selectivity toward σ2 receptors. In this study, we explored the potential of SYA013 in modulating the important biological events associated with cell survival and progression as well as the mechanistic aspects of apoptosis in a representative TNBC cell line (MDA-MB-231). Our results indicate that SYA013 inhibits the proliferation of MDA-MB-231 cells in a concentration-dependent manner and suppresses cell migration and invasion. Apoptotic studies were also conducted in MDA-MB-468 cells (cells derived from a 51-year old Black female with metastatic adenocarcinoma of the breast.). In addition, we have demonstrated that SYA013 induces MDA-MB-231 cell death through the intrinsic apoptotic pathway and may suppress tumor progression and metastasis. Taken together, our study presents a mechanistic pathway of the anticancer properties of SYA013 against TNBC cell lines and suggests a potential for exploring SYA013 as a lead agent for development against TNBC.

Dataset Information

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

Publications

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

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