Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves specialized cells of the immune system able to clear sources of cell injury and damaged tissues ...to promote repair. Excessive inflammation can occur as a result of infections and is a hallmark of several diseases. The molecular basis underlying inflammatory responses are not fully understood. Here, we show that the cell surface marker CD44, which characterizes activated immune cells, acts as a metal transporter that promotes copper uptake. We identified a chemically reactive pool of copper(II) in mitochondria of inflammatory macrophages that catalyzes NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD + enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with a rationally-designed dimer of metformin triggers distinct metabolic and epigenetic states that oppose macrophage activation. This drug reduces inflammation in mouse models of bacterial and viral (SARS-CoV-2) infections, improves well-being and increases survival. Identifying mechanisms that regulate the plasticity of immune cells provides the means to develop next-generation medicine. Our work illuminates the central role of copper as a regulator of cell plasticity and unveils a new therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.
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We have synthesized a collection of quinolizinium fluorescent dyes for the purpose of cell imaging. Preliminary biological studies in human U2OS osteosarcoma cancer cells have shown ...that different functional groups appended to the cationic quinolizinium scaffold efficiently modulate photophysical properties but also cellular distribution. While quinolizinium probes are known nuclear staining reagents, we have identified a particular quinolizinium derivative salt that targets the lysosomal compartment. This finding raises the question of predictability of specific organelle targeting from structural features of small molecules.
Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of ...cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.
Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587.
In the version of this article originally published, several co-authors had incorrect affiliation footnote numbers listed in the author list. Tatiana Cañeque and Angelica Mariani should each have ...affiliation numbers 3, 4 and 5, and Emmanuelle Charafe-Jauffret should have number 6. Additionally, there was an extra space in the name of co-author Robert P. St.Onge. These errors have been corrected in the HTML and PDF versions of the paper and the Supplementary Information PDF.
This symposium is the third PSL (Paris Sciences & Lettres) Chemical Biology meeting (2016, 2019, 2023) held at Institut Curie. This initiative originally started at Institut de Chimie des Substances ...Naturelles (ICSN) in Gif‐sur‐Yvette (2013, 2014), under the directorship of Professor Max Malacria, with a strong focus on chemistry. It was then continued at the Institut Curie (2015) covering a larger scope, before becoming the official PSL Chemical Biology meeting. This latest edition was postponed twice for the reasons that we know. This has given us the opportunity to invite additional speakers of great standing. This year, Institut Curie hosted around 300 participants, including 220 on site and over 80 online. The pandemic has had, at least, the virtue of promoting online meetings, which we came to realize is not perfect but has its own merits. In particular, it enables those with restricted time and resources to take part in events and meetings, which can now accommodate unlimited participants. We apologize to all those who could not attend in person this time due to space limitation at Institut Curie.
Third time lucky: After having to be postponed twice, the third PSL Chemical Biology symposium meeting was held at the Institut Curie in Paris and also virtually on 12th and 13th January 2023. Chemical biology, the science of building molecular systems to investigate biology, delivers otherwise inaccessible knowledge and provides the means to control cellular processes with unique spatiotemporal resolution and efficacy.
Cancer stem cells (CSC) constitute a cell subpopulation in solid tumors that is responsible for resistance to conventional chemotherapy, metastasis and cancer relapse. The natural product Salinomycin ...can selectively target this cell niche by directly interacting with lysosomal iron, taking advantage of upregulated iron homeostasis in CSC. Here, inhibitors of the divalent metal transporter 1 (DMT1) have been identified that selectively target CSC by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death with features of ferroptosis. DMT1 inhibitors selectively target CSC in primary cancer cells and circulating tumor cells, demonstrating the physiological relevance of this strategy. Taken together, this opens up opportunities to tackle unmet needs in anti‐cancer therapy.
Blocked by iron: Inhibitors of the divalent metal transporter 1 (DMT1) have been identified that kill cancer stem cells by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death. Taken together, this provides opportunities for the development of new cancer treatment modalities involving DMT1 inhibitors.
Salinomycin (1) exhibits a large spectrum of biological activities including the capacity to selectively eradicate cancer stem cells (CSC), making it and its derivatives promising candidates for the ...development of drug leads against CSC. It has been previously shown that salinomycin and its C20‐propargylamine derivative (Ironomycin (2)) accumulate in lysosomes and sequester iron in this organelle. Herein, a library of salinomycin derivatives is reported, including products of C20‐amination, C1‐esterification, C9‐oxidation, and C28‐dehydration. The biological activity of these compounds is evaluated against transformed human mammary epithelial HMLER CD24low/CD44high cells, a well‐established model of breast CSC, and HMLER CD24high/CD44low cells deprived of CSC properties. Unlike other structural alterations, derivative 4, which displays a cyclopropylamine at position C20, showed a strikingly low IC50 value of 23 nm against HMLER CD24low/CD44high cells. This study provides highly selective molecules to target the CSC niche, a potential interesting advance for drug development to prevent cancer resistance.
Library of salinomycin derivatives: The search for new candidates to tackle the cancer stem cells (CSC) niche has led to the synthesis of a library of salinomycin derivatives. This study demonstrates that the stereoselective reductive amination at C20 is a key modification for selective targeting of breast CSC. The new C20‐cyclopropylamine derivative exhibited an impressive nanomolar activity against CSC, killing these cells by ROS production, induced after iron accumulation in lysosomes.
Highly symmetric all-metal aromatic Pd3 + complexes can catalyze the cycloisomerization of terminal 1,6-enynes and internal dienynes under mild conditions. Modification of substrates dictates the ...mechanism and steers the reaction toward different polycyclic frameworks, enabling the development of complex cascades. The reactivity of Pd(4/3) complexes is complementary to that of mononuclear Pd(0) and Pd(II) ones.
A comparison of D-π-A+ and D-A+ cationic chromophores based on the quinolizinium system as new acceptor units is reported along with the results of studies into their linear and non-linear optical ...properties and electrochemical data. Experimental and theoretical data show that quinolizinium-based chromophores may provide a new generation of second-order non-linear materials with enhanced performance. The first hyperpolarizabilities were measured by Hyper-Rayleigh scattering experiments and the experimental data are supported by a theoretical analysis. In some chromophores the absence of a bridge (D-A+) between the donor and acceptor fragments enhances the NLO properties and the single crystal structure of such a material has been determined by X-ray diffraction.
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•Design and synthesis of new D-π-A+vs D-A+ chromophores based on quinolizinium cation.•Unbridged D-A+ chromophores with remarkable large beta values.•Cyclic voltammetry measurements compared with DFT calculations.•The work provides valuable hints for rational design of novel D-A+ materials.
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