12 results on '"Icard, Philippe"'
Search Results
2. Citrate targets FBPase and constitutes an emerging novel approach for cancer therapy
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Icard, Philippe, Fournel, Ludovic, Coquerel, Antoine, Gligorov, Joseph, Alifano, Marco, and Lincet, Hubert
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- 2018
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3. Metabolic oscillations during cell-cycle progression.
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Icard, Philippe and Simula, Luca
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CELL cycle , *OSCILLATIONS , *LIGASES , *CANCER cells , *KINASES - Abstract
We discuss how metabolism changes during different phases of the cell cycle to sustain biosynthesis and replication in normal and cancer cells. We also highlight how several master regulators of cell cycle, such as cyclin–cyclin-dependent kinases (cyc–CDK complexes) and E3 proteasome ligases, modulate key metabolic enzymes to support cell-cycle progression. [ABSTRACT FROM AUTHOR]
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- 2022
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4. On the footsteps of Hippocrates, Sanctorius and Harvey to better understand the influence of cold on the occurrence of COVID-19 in European countries in 2020.
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Icard, Philippe, Simula, Luca, Rei, Joana, Fournel, Ludovic, De Pauw, Vincent, and Alifano, Marco
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COVID-19 , *BLOOD circulation , *COVID-19 pandemic , *CLIMATE change , *INFLUENCE , *FOOTSTEPS - Abstract
COVID-19 pandemic has been characterized by a pattern of consecutive declines and regrowth in European countries in 2020. After being partially regressed during the summer, the reappearance of the infection during fall 2020 in many temperate countries strongly suggests that temperature and cold may play a role in influencing the infectivity and virulence of SARS-CoV-2. While promoting medicine as an art, Hippocrates interpreted with logical reasoning the occurrence of diseases such as epidemics, as a consequence of environmental factors, in particular climatic variations. During the Renaissance, Sanctorius was one of the first to perform quantitative measurements, and Harvey discovered the circulation of blood by performing experimental procedures in animals. We think that a reasoning mixing various observations, measurements and experiments is fundamental to understand how cold increases infectivity and virulence of SARS-CoV-2. By this review, we provide evidence linking cold, angiotensin-II, vasoconstriction, hypoxia and aerobic glycolysis (the Warburg effect) to explain how cold affects the epidemiology of COVID-19. Also, a low humidity increases virus transmissibility, while a warm atmosphere, a moderate airway humidity, and the production of vasodilator angiotensin 1-7 by ACE2 are less favorable to the virus entry and/or its development. The meteorological and environmental parameters impacting COVID-19 pandemic should be reintegrated into a whole perspective by taking into account the different factors influencing transmissibility, infectivity and virulence of SARS-CoV-2. To understand the modern enigma represented by COVID-19, an interdisciplinary approach is surely essential. • The influence of climate on COVID-19 pandemic is suspected but largely enigmatic. • Cold may increase viral infectivity by paralyzing airway defense barriers. • Angiotensin II-mediated vasoconstriction induced by cold promotes hypoxia in cells. • Hypoxia activates aerobic glycolysis promoting SARS-CoV-2 replication. • This cascade may have favored the spread of COVID-19 in European countries in 2020. [ABSTRACT FROM AUTHOR]
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- 2021
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5. Fructose-1,6-bisphosphate promotes PI3K and glycolysis in T cells?
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Icard, Philippe, Alifano, Marco, Donnadieu, Emmanuel, and Simula, Luca
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T cells , *GLYCOLYSIS , *PHOSPHATIDYLINOSITOL 3-kinases , *CANCER cells , *METABOLISM - Abstract
We propose that fructose-1,6-bisphosphate (F-1,6-BP) promotes a feedback loop between phosphofructokinase-1 (PFK1), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), and PFK2/PFKFB3, which enhances aerobic glycolysis and sustains effector T (T eff) cell activation, while oxidative metabolism is concomitantly downregulated. This regulation, promoted by low citrate and mitochondrial ATP synthesis, also sustains the Warburg effect in cancer cells. [ABSTRACT FROM AUTHOR]
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- 2021
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6. The key role of Warburg effect in SARS-CoV-2 replication and associated inflammatory response.
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Icard, Philippe, Lincet, Hubert, Wu, Zherui, Coquerel, Antoine, Forgez, Patricia, Alifano, Marco, and Fournel, Ludovic
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SARS-CoV-2 , *GLYCOLYSIS , *COVID-19 , *COVID-19 pandemic , *INFLAMMATION , *VIRAL replication - Abstract
Current mortality due to the Covid-19 pandemic (approximately 1.2 million by November 2020) demonstrates the lack of an effective treatment. As replication of many viruses - including MERS-CoV - is supported by enhanced aerobic glycolysis, we hypothesized that SARS-CoV-2 replication in host cells (especially airway cells) is reliant upon altered glucose metabolism. This metabolism is similar to the Warburg effect well studied in cancer. Counteracting two main pathways (PI3K/AKT and MAPK/ERK signaling) sustaining aerobic glycolysis inhibits MERS-CoV replication and thus, very likely that of SARS-CoV-2, which shares many similarities with MERS-CoV. The Warburg effect appears to be involved in several steps of COVID-19 infection. Once induced by hypoxia, the Warburg effect becomes active in lung endothelial cells, particularly in the presence of atherosclerosis, thereby promoting vasoconstriction and micro thrombosis. Aerobic glycolysis also supports activation of pro-inflammatory cells such as neutrophils and M1 macrophages. As the anti-inflammatory response and reparative process is performed by M2 macrophages reliant on oxidative metabolism, we speculated that the switch to oxidative metabolism in M2 macrophages would not occur at the appropriate time due to an uncontrolled pro-inflammatory cascade. Aging, mitochondrial senescence and enzyme dysfunction, AMPK downregulation and p53 inactivation could all play a role in this key biochemical event. Understanding the role of the Warburg effect in COVID-19 can be essential to developing molecules reducing infectivity, arresting endothelial cells activation and the pro-inflammatory cascade. • Enhanced aerobic glycolysis supports replication of many viruses including MERS-CoV. • PI3K/AKT and MAPK/ERK inhibitors arrest MERS-CoV replication. • This metabolism likely sustains SARS-CoV-2 replication in host cells, in particular airway cells. • The Warburg effect also supports activation of endothelial cells and pro-inflammatory cells. [ABSTRACT FROM AUTHOR]
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- 2021
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7. The reduced concentration of citrate in cancer cells: An indicator of cancer aggressiveness and a possible therapeutic target
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Lincet Hubert, Icard Philippe, Biologie et Thérapies Innovantes des Cancers Localement Agressifs (BioTICLA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pasteur [Nice] (CHU), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Ligue Nationale Contre le Cancer (Comité 69), Service de Chirurgie Thoracique ( NICE - Chirurgie Thoracique ), CHU Nice, Biologie et Thérapies Innovantes des Cancers Localement Agressifs ( BioTICLA ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Institut des Sciences Pharmaceutiques et Biologiques ( ISPB ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Lincet, Hubert, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Cancer Research ,ATP citrate lyase ,Apoptosis ,Oxidative Phosphorylation ,Epigenesis, Genetic ,0302 clinical medicine ,Neoplasms ,Pharmacology (medical) ,Glycolysis ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Lipoic acid ,Prognosis ,Tumor aggressiveness ,Warburg effect ,3. Good health ,ATP-citrate lyase ,Infectious Diseases ,Oncology ,030220 oncology & carcinogenesis ,Intracellular ,medicine.drug ,medicine.medical_specialty ,Hydroxycitrate ,Citric Acid Cycle ,Biology ,Prognosis biomarker ,Citric Acid ,03 medical and health sciences ,Acetyl Coenzyme A ,Internal medicine ,[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology ,Biomarkers, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Pharmacology ,Cisplatin ,Cancer ,medicine.disease ,030104 developmental biology ,Endocrinology ,Cancer cell ,ATP Citrate (pro-S)-Lyase ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,Citrate ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O 2 (Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth. Because citrate is the donor of acetyl-CoA, its reduced production favors a deacetylation state of proteins favoring resistance to apoptosis and epigenetic changes, both processes contributing to tumor aggressiveness. Citrate levels could be monitored as an indicator of cancer aggressiveness (as already shown in human prostate cancer) and/or could serve as a biomarker for response to therapy. Strategies aiming to increase cytosolic citrate should be developed and tested in humans, knowing that experimental studies have shown that administration of citrate and/or inhibition of ACLY arrest tumor growth, inhibit the expression of the key anti-apoptotic factor Mcl-1, reverse cell dedifferentiation and increase sensibility to cisplatin.
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- 2016
8. The dual role of citrate in cancer.
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Icard, Philippe, Simula, Luca, Zahn, Grit, Alifano, Marco, and Mycielska, Maria E.
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CITRATES , *KREBS cycle , *LIPID synthesis , *BONE growth , *METABOLIC models - Abstract
Citrate is a key metabolite of the Krebs cycle that can also be exported in the cytosol, where it performs several functions. In normal cells, citrate sustains protein acetylation, lipid synthesis, gluconeogenesis, insulin secretion, bone tissues formation, spermatozoid mobility, and immune response. Dysregulation of citrate metabolism is implicated in several pathologies, including cancer. Here we discuss how cancer cells use citrate to sustain their proliferation, survival, and metastatic progression. Also, we propose two paradoxically opposite strategies to reduce tumour growth by targeting citrate metabolism in preclinical models. In the first strategy, we propose to administer in the tumor microenvironment a high amount of citrate, which can then act as a glycolysis inhibitor and apoptosis inducer, whereas the other strategy targets citrate transporters to starve cancer cells from citrate. These strategies, effective in several preclinical in vitro and in vivo cancer models, could be exploited in clinics, particularly to increase sensibility to current anti-cancer agents. [ABSTRACT FROM AUTHOR]
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- 2023
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9. How the Warburg effect supports aggressiveness and drug resistance of cancer cells?
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Icard, Philippe, Shulman, Seth, Farhat, Diana, Steyaert, Jean-Marc, Alifano, Marco, and Lincet, Hubert
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Cancer cells employ both conventional oxidative metabolism and glycolytic anaerobic metabolism. However, their proliferation is marked by a shift towards increasing glycolytic metabolism even in the presence of O 2 (Warburg effect). HIF1, a major hypoxia induced transcription factor, promotes a dissociation between glycolysis and the tricarboxylic acid cycle, a process limiting the efficient production of ATP and citrate which otherwise would arrest glycolysis. The Warburg effect also favors an intracellular alkaline pH which is a driving force in many aspects of cancer cell proliferation (enhancement of glycolysis and cell cycle progression) and of cancer aggressiveness (resistance to various processes including hypoxia, apoptosis, cytotoxic drugs and immune response). This metabolism leads to epigenetic and genetic alterations with the occurrence of multiple new cell phenotypes which enhance cancer cell growth and aggressiveness. In depth understanding of these metabolic changes in cancer cells may lead to the development of novel therapeutic strategies, which when combined with existing cancer treatments, might improve their effectiveness and/or overcome chemoresistance. [ABSTRACT FROM AUTHOR]
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- 2018
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10. The metabolic cooperation between cells in solid cancer tumors.
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Icard, Philippe, Kafara, Perrine, Steyaert, Jean-Marc, Schwartz, Laurent, and Lincet, Hubert
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STROMAL cells , *TUMOR growth , *GLUCOSE metabolism , *CANCER cell proliferation , *GLUTAMINE , *FATTY acid synthesis , *ADENOSINE triphosphate , *DRUG development - Abstract
Cancer cells cooperate with stromal cells and use their environment to promote tumor growth. Energy production depends on nutrient availability and O2 concentration. Well-oxygenated cells are highly proliferative and reorient the glucose metabolism towards biosynthesis, whereas glutamine oxidation replenishes the TCA cycle coupled with OXPHOS-ATP production. Glucose, glutamine and alanine transformations sustain nucleotide and fatty acid synthesis. In contrast, hypoxic cells slow down their proliferation, enhance glycolysis to produce ATP and reject lactate which is recycled as fuel by normoxic cells. Thus, glucose is spared for biosynthesis and/or for hypoxic cell function. Environmental cells, such as fibroblasts and adipocytes, serve as food donors for cancer cells, which reject waste products (CO2, H+, ammoniac, polyamines...) promoting EMT, invasion, angiogenesis and proliferation. This metabolic-coupling can be considered as a form of commensalism whereby non-malignant cells support the growth of cancer cells. Understanding these cellular cooperations within tumors may be a source of inspiration to develop new anti-cancer agents. [ABSTRACT FROM AUTHOR]
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- 2014
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11. Why may citrate sodium significantly increase the effectiveness of transarterial chemoembolization in hepatocellular carcinoma?
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Icard, Philippe, Simula, Luca, Wu, Zherui, Berzan, Diana, Sogni, Philippe, Dohan, Anthony, Dautry, Raphael, Coquerel, Antoine, Lincet, Hubert, Loi, Mauro, and Fuks, David
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Hepatocellular carcinoma (HCC) represents the third cause of cancer death in men worldwide, and its increasing incidence can be explained by the increasing occurrence of non-alcoholic steatohepatitis (NASH). HCC prognosis is poor, as its 5-year overall survival is approximately 18 % and most cases are diagnosed at an inoperable advanced stage. Moreover, tumor sensitivity to conventional chemotherapeutics (particularly to cisplatin-based regimen), trans-arterial chemoembolization (cTACE), tyrosine kinase inhibitors, anti-angiogenic molecules and immune checkpoint inhibitors is limited. Oncogenic signaling pathways, such as HIF-1α and RAS/PI3K/AKT, may provoke drug resistance by enhancing the aerobic glycolysis ("Warburg effect") in cancer cells. Indeed, this metabolism, which promotes cancer cell development and aggressiveness, also induces extracellular acidity. In turn, this acidity promotes the protonation of drugs, hence abrogating their internalization, since they are most often weakly basic molecules. Consequently, targeting the Warburg effect in these cancer cells (which in turn would reduce the extracellular acidification) could be an effective strategy to increase the delivery of drugs into the tumor. Phosphofructokinase-1 (PFK1) and its activator PFK2 are the main regulators of glycolysis, and they also couple the enhancement of glycolysis to the activation of key signaling cascades and cell cycle progression. Therefore, targeting this "Gordian Knot" in HCC cells would be of crucial importance. Here, we suggest that this could be achieved by citrate administration at high concentration, because citrate is a physiologic inhibitor of PFK1 and PFK2. As shown in various in vitro studies, including HCC cell lines, administration of high concentrations of citrate inhibits PFK1 and PFK2 (and consequently glycolysis), decreases ATP production, counteracts HIF-1α and PI3K/AKT signaling, induces apoptosis, and sensitizes cells to cisplatin treatment. Administration of high concentrations of citrate in animal models (including Ras-driven tumours) has been shown to effectively inhibit cancer growth, reverse cell dedifferentiation, and neutralize intratumor acidity, without apparent toxicity in animal studies. Citrate may also induce a rapid secretion of pro-inflammatory cytokines by macrophages, and it could favour the destruction of cancer stem cells (CSCs) sustaining tumor recurrence. Consequently, this "citrate strategy" could improve the tumor sensitivity to current treatments of HCC by reducing the extracellular acidity, thus enhancing the delivery of chemotherapeutic drugs into the tumor. Therefore, we propose that this strategy should be explored in clinical trials, in particular to enhance cTACE effectiveness. [ABSTRACT FROM AUTHOR]
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- 2021
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12. Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update.
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Icard, Philippe, Coquerel, Antoine, Wu, Zherui, Gligorov, Joseph, Fuks, David, Fournel, Ludovic, Lincet, Hubert, and Simula, Luca
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ACETYLCOENZYME A , *GLYCOLYSIS , *CANCER cells , *CELL metabolism , *PROTEIN-tyrosine kinase inhibitors , *CITRATES , *NUCLEOTIDE synthesis - Abstract
Citrate plays a central role in cancer cells' metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies. [ABSTRACT FROM AUTHOR]
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- 2021
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