Bis(4-hydroxy-2H-chromen-2-one) Coumarin Induces Apoptosis in MCF-7 Human Breast Cancer Cells Through Aromatase Inhibition

AIM: The present investigation aimed to examine the therapeutic potential of the new coumarin derivative bis(4-hydroxy-2H-chromen-2-one) coumarin (4HC) against breast cancer. MATERIALS AND METHODS: For this purpose, the effects of 4HC treatment on the proliferation of MCF-7 breast cancer cells and on MCF-10a non-cancerous cells were evaluated using a fluorescent assay. Cell cycle distribution and apoptosis were measured by image cytometry. The expression level of aromatase (CYP19A1) and apoptosis-related genes were determined by real-time PCR. RESULTS: MCF-7 mammary cancer cell proliferation was significantly decreased within 24 h after treatment with 4HC at 50 muM, while no effect was observed on the viability of MCF-10a non-cancerous mammary cells. 4HC also increased the percentage of the cells in the G2/M phase, inducing apoptosis. Real-time PCR revealed that 4HC induced MCF-7 mortality through an up-regulation of Bax and a down-regulation of Bcl-2, resulting in an increase in caspase-3 gene expression. The increased expression of apoptosis-related genes was accompanied by a decrease in CYP19A1 gene expression. CONCLUSION: 4HC selectively inhibits proliferation of MCF-7cells in vitro. Moreover, 4HC has inhibitory effects on aromatase gene expression and promoting effects on apoptosis, in MCF-7 cells

Bis(4-hydroxy-2H-chromen-2-one) CoumarinInduces Apoptosis in MCF-7 Human BreastCancer Cells Through Aromatase Inhibition

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Cytostatic hydroxycoumarin OT52 induces ER/Golgi stress and STAT3 inhibition triggering non-canonical cell death and synergy with BH3 mimetics in lung cancer.

Coumarins are natural compounds with antioxidant, anti-inflammatory and anti-cancer potential known to modulate inflammatory pathways. Here, non-toxic biscoumarin OT52 strongly inhibited proliferation of non-small cell lung cancer cells with KRAS mutations, inhibited stem-like characteristics by reducing aldehyde dehydrogenase expression and abrogated spheroid formation capacity. This cytostatic effect was characterized by cell cycle arrest and onset of senescence concomitant with endoplasmic reticulum and Golgi stress, leading to metabolic alterations. Mechanistically, this cellular response was associated with the novel capacity of biscoumarin OT52 to inhibit STAT3 transactivation and expression of its target genes linked to proliferation. These results were validated by computational docking of OT52 to the STAT3 DNA-binding domain. Combination treatments of OT52 with subtoxic concentrations of Bcl-xL and Mcl-1-targeting BH3 protein inhibitors triggered synergistic immunogenic cell death validated in colony formation assays as well as in vivo by zebrafish xenografts

Hydroxycoumarin OT-55 kills CML cells alone or in synergy with imatinib or Synribo: Involvement of ER stress and DAMP release

We synthetized and investigated the anti-leukemic potential of the novel cytostatic bis(4-hydroxycoumarin) derivative OT-55 which complied with the Lipinski's rule of 5 and induced differential toxicity in various chronic myeloid leukemia (CML) cell models. OT-55 triggered ER stress leading to canonical, caspase-dependent apoptosis and release of danger associated molecular patterns. Consequently, OT-55 promoted phagocytosis of OT-55-treated CML cells by both murine and human monocyte-derived macrophages. Moreover, OT-55 inhibited tumor necrosis factor α-induced activation of nuclear factor-кB and produced synergistic effects when used in combination with imatinib to inhibit colony formation in vitro and Bcr-Abl+ patient blast xenograft growth in zebrafish. Furthermore, OT-55 synergized with omacetaxine in imatinib-resistant KBM-5 R cells to inhibit the expression of Mcl-1, triggering apoptosis. In imatinib-resistant K562 R cells, OT-55 triggered necrosis and blocked tumor formation in zebrafish in combination with omacetaxine

Hydroxycoumarin OT-55 kills CML cells alone or in synergy with imatinib or Synribo: Involvement of ER stress and DAMP release

We synthetized and investigated the anti-leukemic potential of the novel cytostatic bis(4-hydroxycoumarin) derivative OT-55 which complied with the Lipinski's rule of 5 and induced differential toxicity in various chronic myeloid leukemia (CML) cell models. OT-55 triggered ER stress leading to canonical, caspase-dependent apoptosis and release of danger associated molecular patterns. Consequently, OT-55 promoted phagocytosis of OT-55-treated CML cells by both murine and human monocyte-derived macrophages. Moreover, OT-55 inhibited tumor necrosis factor α-induced activation of nuclear factor-кB and produced synergistic effects when used in combination with imatinib to inhibit colony formation in vitro and Bcr-Abl+ patient blast xenograft growth in zebrafish. Furthermore, OT-55 synergized with omacetaxine in imatinib-resistant KBM-5 R cells to inhibit the expression of Mcl-1, triggering apoptosis. In imatinib-resistant K562 R cells, OT-55 triggered necrosis and blocked tumor formation in zebrafish in combination with omacetaxine

The European dRTA Registry: an initial data analysis

BACKGROUND AND AIMS: Distal renal tubular acidosis (dRTA) is a rare disorder characterised by an inability of the distal tubule to secrete acid, leading to metabolic acidosis. Clinical consequences typically include hypokalaemia, hypercalciuria with nephrocalcinosis and/or urolithiasis, as well as bone disease. Treatment with adequate alkali supplementation corrects the acidosis and hypercalciuria, but there are few data on long-term outcome. In 2018, a registry for dRTA was established by the European Society for Paediatric Nephrology, hosted by the European Rare Kidney Disease Reference Network. Here, we present an initial analysis of data in the registry. METHOD: Analysis of data entered into the registry by the cut-off data of 18/11/2020. RESULTS: A total of 135 patients had been entered, of which 106 had additional data from an annual follow-up visit. Median age at last visit was 10 years (range 0-54), including 16 adults (>17y). Genetic testing had been performed in 91 subjects and causative variants were reported in 74 (81%). Pertinent clinical details according to genetic group are listed in table 1. Treatment was provided with at least 15 different preparations, containing citrate or bicarbonate, given in 1-10 (median 3) daily doses. Adequate treatment at last follow-up, as judged by a plasma bicarbonate level >21 mmol/l and a urine calcium-creatinine ratio in the age-specific normal range was present in 46% of subjects. There was a trend for higher eGFR and height SDS in subjects with adequate treatment compared to those without, but this was not statistically significant. CONCLUSION: Currently available data demonstrate the difficulties in treating dRTA, with less than half of subjects achieving adequate control of their acidosis. By collecting long-term data, the registry will provide important information on the prognosis and complications of dRTA and to what degree these can be prevented with treatment. Enrollment of further, especially adult patients will contribute to our understanding of this rare disorder

Mission archéologique de Madâ'in Sâlih (Arabie Saoudite) : Recherches menées de 2001 à 2003 dans l'ancienne Hijrâ des Nabatéens

84 pagesInternational audienceThis contribution presents the preliminary results of the Madâ'in Sâlih archaeological project, which started in 2001 and which, in December 2004, completed its fourth field season. The aims of this five-year project are a systematic recording of the archaeological remains at the site as well as an analysis of its agricultural potential. The former include not only the tombs, sanctuaries, wells, quarries, walls, buildings, etc., but also the inscriptions written in various scripts and languages. Parallel to this exploration of what is visible on the surface, an extensive geophysical survey was undertaken in the so-called residential area, in the central part of the site, in order to obtain an image of the sub-surface remains. This contribution begins with a presentation of the sources, followed by a brief history of the exploration of Madâ'in Sâlih. The focus is on the conditions which allowed this project to be established as well as the problematics which guided it. J.-B. Rigot then presents his analysis of the agricultural potential of the site, demonstrating the existence, in antiquity, of a large oasis. Finally, a preliminary description of the main components of the sites: the necropoleis, the sanctuaries and the residential area, is given

On the Runtime Enforcement of Timed Properties

International audienceRuntime enforcement refers to the theories, techniques, and tools for enforcing correct behavior of systems at runtime. We are interested in such behaviors described by specifications that feature timing constraints formalized in what is generally referred to as timed properties. This tutorial presents a gentle introduction to runtime enforcement (of timed properties). First, we present a taxonomy of the main principles and concepts involved in runtime enforcement. Then, we give a brief overview of a line of research on theoretical runtime enforcement where timed properties are described by timed automata and feature uncontrollable events. Then, we mention some tools capable of runtime enforcement, and we present the TiPEX tool dedicated to timed properties. Finally, we present some open challenges and avenues for future work. Runtime Enforcement (RE) is a discipline of computer science concerned with enforcing the expected behavior of a system at runtime. Runtime enforcement extends the traditional runtime verification [12-14, 42, 43] problem by dealing with the situations where the system deviates from its expected behavior. While runtime verification monitors are execution observers, runtime enforcers are execution modifiers. Foundations for runtime enforcement were pioneered by Schneider in [98] and by Rinard in [95] for the specific case of real-time systems. There are several tutorials and overviews on runtime enforcement for untimed systems [39, 47, 59], but none on the enforcement of timed properties (for real-time systems). In this tutorial, we focus on runtime enforcing behavior described by a timed property. Timed properties account for physical time. They allow expressing constraints on the time that should elapse between (sequences of) events, which is useful for real-time systems when specifying timing constraints between statements, their scheduling policies, the completion of tasks, etc [5, 7, 88, 101, 102]. This tutorial comprises four stages: 1. the presentation of a taxonomy of concepts and principles in RE (Sec. 1); 2. the presentation of a framework for the RE of timed properties where specifications are described by timed automata (preliminary concepts are recalled in Sec. 2, the framework is overviewed in Sec. 3, and presented in more details in Sec. 4); 3. the demonstration of the TiPEX [82] tool implementing the framework (Sec. 5); 4. the description of some avenues for future work (Sec. 6)