Dataset Information

Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model

ABSTRACT: Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system xc-. Among the existing system xc- inhibitors, imidazole ketone erastin (IKE) is a potent, metabolically stable inhibitor of system xc- and inducer of ferroptosis potentially suitable for in vivo applications. We investigated the pharmacokinetic and pharmacodynamic features of IKE in a diffuse large B cell lymphoma (DLBCL) xenograft model and demonstrated that IKE exerted an antitumor effect by inhibiting system xc-, leading to glutathione depletion, lipid peroxidation, and the induction of ferroptosis biomarkers both in vitro and in vivo. Using untargeted lipidomics and qPCR, we identified distinct features of lipid metabolism in IKE-induced ferroptosis. In addition, biodegradable polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles were employed to aid in IKE delivery and exhibited reduced toxicity compared with free IKE in a DLBCL xenograft model.

INSTRUMENT(S): Liquid Chromatography MS - Negative (LC-MS (Negative)), Liquid Chromatography MS - Positive (LC-MS (Positive))

SUBMITTER: Fereshteh Zandkarimi

PROVIDER: MTBLS774 | MetaboLights | 2019-04-17

REPOSITORIES: MetaboLights

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Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model.

Zhang Yan Y Tan Hui H Daniels Jacob D JD Zandkarimi Fereshteh F Liu Hengrui H Brown Lewis M LM Uchida Koji K O'Connor Owen A OA Stockwell Brent R BR

Cell chemical biology 20190221 5

Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system xc-. Among the existing system xc- inhibitors, imidazole ketone erastin (IKE) is a potent, metabolically stable inhibitor of system xc- and inducer of ferroptosis potentially suitable for in vivo applications. We investigated the pharmacokinetic and pharmacodynamic features of IKE in a diffuse large B cell ly ...[more]

PMID: 30799221

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Project description:Introduction: The flavonoid myricetin has been shown to induce cell cycle arrest and mitochondrial-dependent apoptosis in preclinical cancer models. We hypothesised that myricetin-derived flavonoids with redox properties and improved physicochemical attributes that enhance cell uptake and mitochondrial targeting might have increased potential as antitumour agents, since mitochondria are the main site of production of reactive oxygen species (ROS) and redox status is known to regulate the development and advancement of certain cancers. In this study we assessed a small library of novel flavonoids, then focussed on the lead compound, second-generation analogue OncamexTM, its mechanism of action and structure-activity relationships as an anti-proliferative agent. Methods: With this aim, we studied the effect of OncamexTM in a panel of 7 breast cancer cell lines using proliferation, cytotoxicity and apoptosis assays. The redox properties and mitochondrial delivery of the drug were studied using cyclic voltammetry and fluorescence microscopy, respectively. The mechanism of action was further studied using western blotting, gene expression analysis and immunohistochemistry (IHC) of treated xenograft tissue from in vivo mice models. Results: Sulforhodamine B (SRB) proliferation assays demonstrated strong, anti-proliferative properties of OncamexTM, with IC50 values in the low micromolar range. Treatment for 8 h exerted concentration-dependent reduction in cell viability and induction of cytotoxicity and apoptosis, with increased caspase activation. Microarray analysis suggested that OncamexTM regulates changes in cell cycle and apoptosis at gene expression level. Fluorescence microscopy was used to investigate mitochondrial targeting and ROS regulation in treated cells. OncamexTM was found to induce production of superoxide at concentrations which exerted anti-proliferative effects. Initial in vivo studies in mice implanted with a MDA-MB-231 breast cancer xenograft showed that OncamexTM inhibited tumour growth, reducing tissue viability and Ki-67 proliferation, with no overall systemic toxicity. Conclusions: OncamexTM is a novel flavonoid capable of specific delivery to the mitochondria and induction of ROS production. We have shown its antitumor activity in preclinical models of breast cancer, both in vitro and in initial in vivo models, where tumour growth was arrested without inducing toxicity, support the potential of this novel drug for its continued development as an anticancer agent. Total RNA was obtained from 5 breast cancer cell lines subjected to 6 hours of 10µM OncamexTM and matched untreated controls (1% DMSO)

Dataset Information

Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model

Publications

Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model.

Similar Datasets

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