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

Nayeem, Nazia; Yeasmin, Arefa; Cobos, Samantha N.; Younes, Ali; Hubbard, Karen; Contel, Marı́a

doi:10.1002/cmdc.202100325

Cited by 6 publications

(24 citation statements)

References 61 publications

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“…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).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…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).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…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.…”

Section: ■ Introductionmentioning

confidence: 99%

“…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.…”

Section: ■ Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition

Zhang,

Wang,

et al. 2024

Journal of Inorganic Biochemistry

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Elucidating the Multimodal Anticancer Mechanism of an Organometallic Terpyridine Platinum(II) N-Heterocyclic Carbene Complex against Triple-Negative Breast Cancer In Vitro and In Vivo

Zhang

Schmidt

et al. 2023

J. Med. Chem.

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Treatment of triple-negative breast cancer (TNBC) has long been a medical challenge because of the lack of effective therapeutic targets. Targeting lipid, carbohydrate, and nucleotide metabolism pathways has recently been proven as a promising option in view of three heterogeneous metabolic-pathway-based TNBC subtypes. Here, we present a multimodal anticancer platinum(II) complex, named Pt(II)caffeine, with a novel mode of action involving simultaneous mitochondrial damage, inhibition of lipid, carbohydrate, and nucleotide metabolic pathways, and promotion of autophagy. All these biological processes eventually result in a strong suppression of TNBC MDA-MB-231 cell proliferation both in vitro and in vivo. The results indicate that Pt(II)caffeine, influencing cellular metabolism at multiple levels, is a metallodrug with increased potential to overcome the metabolic heterogeneity of TNBC.

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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

Cited by 6 publications

References 61 publications

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

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

Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition

Elucidating the Multimodal Anticancer Mechanism of an Organometallic Terpyridine Platinum(II) N-Heterocyclic Carbene Complex against Triple-Negative Breast Cancer In Vitro and In Vivo

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