Éditeur(s) : HAL CCSD
Résumé : Background and objectives.[br/] Dairy propionibacteria are isolated from various ecological niches, including soil, grass, silage, rumen, raw milk and dairy plants, showing great adaptability and robustness. Used as ripening starters in Swiss type cheeses, these food grade bacteria are described as nutraceutical producers and they release into the external medium short chain fatty acids (SCFA), folic acid, cobalamin and the bifidogenic 1,4- dihydroxy-2-naphthoic acid (DHNA). These compounds are known to play a pivotal role in the modulation of intestinal physiology through diet. Considering the pro-apoptotic potential of some of these metabolites, we investigated the potential of dairy products fermented by the main species, Propionibacterium freudenreichii, to prevent colon carcinogenesis. Methods.[br/] We developed a new fermented milk. Taking advantage of milk fractions, high and stable populations of P. freudenreichii were obtained in this product. It was tested in vitro on gastric HGT-1 and colic HT-29 cells with respect to the typical hallmarks of apoptosis. In vivo, the fermented milk was evaluated in piglets with respect to general health parameters and in human microbiota-associated rats, treated or not with dimethylhydrazine (DMH), with respect to intestinal proliferation and apoptosis. Results. Fermented milk induced cell death in both gastric and colon cancer cells. Cellular and molecular characterization of cells dying in response to SCFA treatment revealed cell cycle arrest, drop in intracellular ATP, depolarization of mitochondria, translocation of key apoptosis proteins, processing of caspases and fragmentation of the nucleus. Interestingly, the new fermented milk was shown to potentiate the cytotoxic effect of molecules used in cancer chemotherapy. In accordance, it modulated expression of key apoptotic proteins. In vivo, the fermented milk was evaluated in piglets. Daily oral gavage led to high colic P. freudenreichii populations, to modulation of the intestinal microbiota and modulation of intestinal cytokines. Promotion of piglets’ growth also revealed general probiotic effects of fermented milk. Considering that propionibacteria were metabolically active in the intestine, we further investigated their impact on colon carcinogenesis (induced by dimethylhydrazine, DMH) in human microbiota-associated rats. Consumption of selected strains of propionibacteria resulted in enhanced apoptotic depletion of DMH damaged epithelial cells, yet had no effect on neither proliferation nor apoptosis in healthy rats. Conclusions and perspectives.[br/] These results open new perspectives in the field of colon cancer cells prevention and/or treatment. The synergy with pro-apoptotic chemotherapy molecules suggests that such a fermented product may be proposed as a food supplement to enhance the effects of anticancer treatments.
colloque international « Nutrition and Cancer : Hot topics from biology to public health issues »
Paris, France

hal-01190452
https://hal.archives-ouvertes.fr/hal-01190452
PRODINRA : 201853

Éditeur(s) : HAL CCSD
Résumé : Croton urucurana Baillon (Euphorbiaceae), plant species popularly known in Brazil as “sangra-d’água”, is commonly found in Mato Grosso do Sul State (midwestern Brazil), where its latex is popularly used to treat several types of cancer. Despite the ethnopharmacological significance of the species, no phytochemical or cytotoxic studies of its latex have been published. In this context, the aim of the present study was to assess the cytotoxic activity of crude extracts, fractions and isolated compound from the latex of C. urucurana and to investigate the effects of crourorb A1 on the viability, apoptosis, cell cycle and cell migration of human hepatocarcinoma cell lines (Huh-7). Also, we have evaluated the viability of Huh-7 cells treated with crourorb A1 in 3D collagen gels. The cytotoxicity was detected using the sulforhodamine B (SRB) assay against six human cancer cells lines and one nontumor NIH/3T3 cell line (murine fibroblast). Studies on the mechanism of cell death of crourorb A1 were conducted in different test systems in vitro. The bioactive ethyl acetate phase obtained from the latex of C. urucurana afforded a novel cyclic peptide, [1−9-NαC]-crourorb A1, that proved active against NCIADR/ RES (ovary, multidrug-resistance phenotype) cells with the same potency as doxorubicin (positive control) and inactive up to the highest concentration tested against nontumor NIH/3T3 cells (GI50 = > 250 μg/mL). Crourorb A1 treatment decreases the cell viability of Huh-7 at dose and time dependent manner associated with induction of apoptosis by caspase 3/7 activation and increasing expression of pro-apoptotic proteins: Bak, Bid, Bax, Puma, Bim, and Bad and clived-caspase3 protein. The JNK/MAP pathway is involved in this induced cell death. Crourorb A1 effect is also associated with G2/M phase cell cycle arrest. In parallel, we observed that crourorb A1 treatment resulted in an increase of cyclin-dependent kinase (CDK1), cyclin B1 and cyclin D1 expressions. A significant reduction of Huh-7 cells migration by crourorb A1 can be assessed and we also show that cells grown on 3D collagen gels exhibited increased resistance to crourorb A1 when compared to 2D cell culture.
Croton urucurana Baillon (Euphorbiaceae), est une plante très connue et utilisée en médecine traditionnelle au Brésil, la «sangra-d’água» retrouvée dans l'État du Mato Grosso do Sul (région Centre-Ouest du Brésil). Son latex est abondamment utilisé en médecine traditionnelle dans le traitement de plusieurs types de cancer. En dépit de son importance ethnopharmacologique, on ne trouve aucune étude sur sa composition chimique ou sur sa potentielle activité anti-cancéreuse. L’objectif de ce travail a été d'évaluer l'activité cytotoxique des extraits totaux, fractions d’extraits et de molécules purifiées, isolées du latex de C. urucurana. Nous avons étudié plus particulièrement les effets du crourorb A1 sur la viabilité, l'apoptose, le cycle cellulaire et la migration de cellules issues de carcinome hépatocellulaire humaine (Huh-7). Nous avons également évalué l’effet du crourorb A1sur la viabilité des cellules Huh-7 cultivées dans les gels de collagène en 3D. L' activité cytotoxique ont été réalisées par le test à la sulforhodamine B sur six lignées cellulaire cancéreuses et sur une lignée cellulaire non cancéreuse de fibroblastes murins, les cellules NIH/3T3. L'étude phytochimique de la fraction ‘acétate d'éthyle’ du latex de C. urucurana bioguidé a permis d’obtenir un nouveau cyclopeptide que nous avons nommé [1-9-NαC]-crourorb A1. Le crourorb présente une cytotoxicité puissante sur la lignée cellulaire cancéreuse NCI-ADR/RES (ovaire, le phénotype de multirésistance) à un niveau équivalent à celle de la doxorubicine (témoin positif). Ce composé est de plus pratiquement inactif (GI50 = >250 μg/mL) sur la lignée non cancéreuse NIH/3T3. L'évaluation de la cytotoxicité in vitro du crourorb A1 (test wst1) sur les cellules Huh-7 a démontré que la viabilité des cellules est inhibée de manière dose et temps-dépendant. Nous avons mesuré une forte activation des caspases 3 et 7 et une nette augmentation de l’expression des protéines pro-apoptotiques (Bak, Bid, Bax, Puma, Bim et Bad) ainsi que de la caspase 3 clivée par le crourorb A1. Nous avons également déterminé que la voie de signalisation JNK-MAPkinase semble nécessaire à l’induction de la mort cellulaire des cellules Huh-7 traitées au crourorb A1. Le crourob A1 induit un arrêt du cycle cellulaire en phase G2/M. En parallèle, les expressions de la cycline-dépendante kinase CDK1, des cyclines B1 et D1 sont augmentées après traitement au crourorb A1. De plus, le crourorb A1 a un effet inhibiteur significatif de la migration des cellules Huh-7, en présence ou absence de mitomycine C. Nous avons également confirmé, l’effet inhibiteur du crourob A1 sur la viabilité des cellules Huh7 cultivées en 3D dans les gels de collagène 1 et démontré que les cellules cultivées en 3D semblent plus résistantes au crourorb A1 par rapport aux cultures en monocouche 2D.
Croton urucurana Baillon (Euphorbiaceae) é uma espécie arbórea conhecida popularmente no Brasil como “sangra d´água”, comumente encontrada no estado de Mato Grosso do Sul, onde seu látex tem sido utilizado na medicina popular no tratamento de vários tipos de câncer. Apesar de sua importância etnofarmacológica, não há relatos de estudos relacionados à sua composição química ou atividades anticâncer na literatura. Nesse contexto, o objetivo do presente estudo foi avaliar a atividade citotóxica de extratos, fases, frações e da substância isolada do látex de C. ururucurana e investigar os mecanismos celulares e moleculares in vitro responsáveis pela citotoxicidade da substância isolada considerando seu potencial apoptótico e influência sobre a progressão do ciclo celular em uma linhagem de hepatocarcinoma celular humano (Huh-7), bem como, os efeitos desta substância sobre a migração e viabilidade de células Huh-7 cultivadas em geis de colágeno em 3D. O ensaio de citotoxicidade in vitro foi realizado com o corante sulforrodamina B (SRB) em seis linhagens de células neoplásicas humanas e uma linhagem de células não neoplásicas NIH/3T3 (fibloblasto murinho). Os estudos de mecanismos de ação com crourorb A1 foram conduzidos em diferentes sistemas-teste in vitro. O estudo fitoquímico biomonitorado da fase bioativa acetato de etila do látex de C. urucurana resultou no isolamento de um novo ciclopeptídeo denominado [19-NαC]-crourorb A1, que apresentou potente atividade citotóxica frente à linhagem de células neoplásicas NCI-ADR/RES (ovário com fenótipo de resistência a múltiplos fármacos), com a mesma potência que a doxorrubicina (controle positivo), e foi inativa até a maior concentração testada (GI50 = >250 μg/mL) frente à linhagem de células não neoplásicas 3T3. A exposição de células Huh-7 ao crourorb A1 resultou em uma diminuição da viabilidade celular de maneira dose e tempo-dependentes. Nós observamos um aumento da atividade de caspases 3 e 7 e um aumento da expressão de proteínas próapoptóticas (Bak, Bid, Bax, Puma, Bim e Bad) e caspase 3 clivada após tratamento com crourorb A1. Além disso, observamos que a via de sinalização celular MAP/JNK foi necessária para induzir a morte celular em células Huh-7 tratadas com crourorb A1. Os efeitos de crourorb A1 foram também associados com o acúmulo de células na fase G2/M do ciclo celular. Em paralelo, as expressões da cinase dependente da ciclina (CDK1), ciclina B1 e ciclina D1 foram aumentadas após tratamento com crourorb A1. Foi demonstrado também o envolvimento de crourorb A1 na redução da migração de células Huh-7 cultivadas na presença e ausência de mitomicina C. A avaliação da viabilidade de células Huh-7 cultivadas em geis de colágeno em 3D apontou uma maior resistência destas células ao crourorb A1 quando comparadas com a cultura de células em 2D.
https://tel.archives-ouvertes.fr/tel-01478286

NNT : 2016REN1B010
tel-01478286
https://tel.archives-ouvertes.fr/tel-01478286
https://tel.archives-ouvertes.fr/tel-01478286/document
https://tel.archives-ouvertes.fr/tel-01478286/file/DE-MATOS-CANDIDO-BACANI-Priscila.pdf

Éditeur(s) : HAL CCSD American Association for Cancer Research
Résumé : International audience
The aim of this study was to test in vitro the efficacy of TAC, an original G-quadruplex ligand, as a potential radiosensitizing agent for glioblastoma multiforme (GBM). Two human radioresistant telomerase-positive GBM cell lines (SF763 and SF767) were analyzed, with and without TAC treatment, for telomere length, cell proliferation, apoptosis, cell-cycle distribution, gene expression, cytogenetic aberrations, clonogenic survival assay, 53BP1 immunofluorescence staining, and γH2AX phosphorylation. We found that low concentrations of TAC (0.5 and 1 μmol/L) inhibited the proliferation of GBM cells in a concentration-dependent manner after only 1 week of treatment, with minimal effects on cell cycle and apoptosis. TAC treatment had no visible effect on average telomere length but modified expression levels of telomere-related genes (hTERT, TRF1, and TRF2) and induced concentration-dependent DNA damage response and dicentric chromosomes. Survival curves analysis showed that exposure to nontoxic, subapoptotic concentrations of TAC enhanced radiation-induced killing of GBM cells. Analysis of DNA repair after irradiation revealed delayed repair kinetics in GBM cells treated with TAC. Furthermore, the combined treatment (TAC and radiation) significantly increased the frequency of chromosomal aberrations as compared with radiation alone. These findings provide the first evidence that exposure to a G4 ligand radiosensitizes human glioblastoma cells and suggest the prospect of future therapeutic applications.
ISSN: 1535-7163

hal-00851184
https://hal.archives-ouvertes.fr/hal-00851184
DOI : 10.1158/1535-7163.MCT-10-0664
PUBMED : 21987532

Éditeur(s) : HAL CCSD
Résumé : Staphylococcus aureus is an opportunistic pathogen of humans and warm-blooded animals. It is foundin healthy carriage and can cause a wide range of infections in its hosts. The epithelial surface is theprincipal site of staphylococcal infection. The pathogens have evolved sophisticated mechanisms tohijack the main function of the host cells, thus promoting their invasion and colonization. Amongstthese effects are, alteration of host cell apoptosis, promotion of cell proliferation or conversely,inhibition of cell growth. Using human cervix cancer HeLa and mammary gland bovine MAC-Tepithelial cells, we studied the cytopathic effect of S. aureus and its ability to affect host cell cycle.Using microscopic examination, we found that S. aureus induced the cytopathic effect resulting in theenlargement of the host cells 72 hours post infection. Our experiments showed that the proliferationrate of the epithelial cells was slowed down in S. aureus-infected culture. Three different S. aureusstrains from human and animal origins were used and showed similar effect on both human and bovinecells. Microscopic analysis of DAPI-stained cells revealed huge decrease of mitotic indexes in infectedHeLa and Mac-T cells, synchronized by Double Thymidine Block. Using flow cytometry analysis, wefound that S. aureus induces G2/M phase delay in synchronous HeLa cells. By Western blot analysis,we showed that the G2/M phase delay was associated with accumulation of inactive phosphorylatedcyclin-dependent kinase Cdk1/cdc2, a key inducer of mitosis entry, and dephosphorylation of corehistone H3, an important component of the epigenetic landscape.These results suggest that the delay in G2/M phase transition of the infected epithelial cells may beone of the mechanisms employed by S. aureus to survive and to propagate inside the host. A fullcomprehension of the mechanisms associated to S. aureus-host cell interactions will undoubtedly helpto discover novel targets to treat staphylococcal infections.
EMBO
Villars sur Ollon, Switzerland

hal-01454214
https://hal.archives-ouvertes.fr/hal-01454214
PRODINRA : 171657

Éditeur(s) : HAL CCSD
Résumé : International audience
We used K562 cells sensitive or generated resistant to imatinib or nilotinib to investigate their response to mycophenolic acid (MPA). MPA induced DNA damage leading to cell death with a minor contribution of apoptosis, as revealed by annexin V labeling (up to 25%). In contrast, cell cycle arrest and positive staining for senescence-associated β-galactosidase activity were detected for a large cell population (80%). MPA-induced cell death was potentialized by the inhibition of autophagy and this is associated to the upregulation of apoptosis. In contrast, senescence was neither decreased nor abrogated in autophagy deficient K562 cells. Primary CD34 cells from CML patients sensitive or resistant to imatinib or nilotinib respond to MPA although apoptosis is mainly detected. These results show that MPA is an interesting tool to overcome resistance in vitro and in vivo mainly in the evolved phase of the disease.
Leukemia Research and Treatment

hal-00846103
https://hal.archives-ouvertes.fr/hal-00846103
https://hal.archives-ouvertes.fr/hal-00846103/document
https://hal.archives-ouvertes.fr/hal-00846103/file/Mycophenolic_Acid_Overcomes-accepted.pdf
PUBMED : 23213550

Éditeur(s) : HAL CCSD
Résumé : Food-grade dairy propionibacteria are nutraceutical producers. They release short chain fatty acids (SCFAs), folic acid and cobalamin, which play a role in intestinal physiology. SCFAs induce apoptosis via the mitochondrial death pathway. We investigated the potential of dairy propionibacteria-fermented products to synergize with drugs used in gastric and colorectal cancer.Fermented milk contained high and viable populations of propionibacteria. This product, as well as its cell-free supernatant, were tested in vitro on gastric HGT-1 and colic HT-29 cells with respect to apoptosis and synergy with known anti-cancer molecules, camptothecin and the human cytokine TRAIL (TNF Related Apoptosis Inducing Ligand). Viability was monitored and apoptosis quantified by Hoescht staining, ROS production, mitochondrial membrane potential perturbation and caspases activity assay. A transcriptomic study on genome-wide microarray was performed in collaboration with the company Miltenyi.Fermented milk induced cell death in both gastric and colon cancer cells. Characterization of cells revealed cell cycle arrest, drop in intracellular ATP, depolarization of mitochondria, translocation of key apoptosis proteins, processing of caspases and fragmentation of the nucleus. Interestingly, the fermented milk was shown to potentiate the cytotoxic effect of molecules used in cancer chemotherapy, camptothecin and TRAIL. The observed synergistic pro-apoptotic effect between TRAIL and propionibacterial SCFAs depended on death receptors and on caspases, was more lethal on cancer cells than on normal human intestinal epithelial cells (HIEC), and was inhibited by Bcl-2 expression. Transcriptomics revealed that propionibacterial metabolites boosted TRAIL-induced modulation of gene expression in human colon cancer cells.These results open new perspectives in the field of colon cancer cells prevention and/or treatment. The synergy with pro-apoptotic chemotherapy molecules suggests that such a fermented product, or the propionibacterium alone, may be proposed as a food supplement to enhance the effects of anticancer treatments.
The 2nd International conference on Cell Death In Cancer (CDIC)
La Baule, France

hal-01209622
https://hal.archives-ouvertes.fr/hal-01209622
PRODINRA : 261291

Éditeur(s) : HAL CCSD
Résumé : The trophic endosymbiosis interaction between a cnidarian host and its photosynthetic dinoflagellatessymbionts form the basis of coral reef ecosystems. Cnidarians host their symbionts in gastrodermis cells, in a phagocytosis-derived vacuole. Establishment and maintenance of the symbiotic interaction depend on an intimate molecular communication between the two partners. However, environmental and/or anthropogenic disturbances can lead to the breakdown of the symbiotic association, which is responsible for the worldwide decline of coral reefs. The main objectives of my research project are to improve the knowledge regarding symbiosis maintenance and disruption mechanisms, but also to define the molecular key players involved at the symbiotic interface in the sea anemone, Anemonia viridis. First, we have described the cellular mechanisms involved in the different types of symbiosis breackdown. Meanwhile, the characterization of npc1 and npc2 genes (involved in endosomal sterol transport), showed a duplication and a sub-functionalization of the npc2d gene. Both NPC1 and NPC2 proteins are expressed around symbionts. We therefore suggest that the duplicated protein NPC2-d is a biomarker of symbiosis health and that NPC1 protein is a marker of the perisymbiotic membrane. We then developed a protocol to characterize the proteome of the symbiotic interface between the two symbiotic partners. The newly-identified symbiotic key players will increase the general knowledge on the symbiotic interaction and its regulation during both stable and bleaching conditions.
L’endosymbiose trophique établie entre un hôte Cnidaire et ses symbiotes Dinoflagellés photosynthétiques est à l’origine du succès évolutif des écosystèmes coralliens. Les symbiotes sont internalisés par un mécanisme de phagocytose et maintenus dans les cellules du gastroderme de l'hôte. La symbiose est régie par un dialogue moléculaire intime entre les deux partenaires, interrompu lors de perturbations environnementales ou anthropiques, responsables du déclin mondial des récifs coralliens. Les objectifs de mon projet de recherche sont de définir les acteurs moléculaires localisés à l’interface symbiotique chez l’anémone de mer, Anemonia viridis. Premièrement, nous avons étudié les mécanismes cellulaires impliqués dans différents types de rupture de la symbiose et mis en évidence des phénomènes d’apoptose, nécrose et symbiophagie. Parallèlement, nous avons caractérisé chez l’anémone les gènes npc1 et npc2, impliqués chez les vertébrés dans le transport endosomal de stérols, et dont l’expression est modulée par l’état symbiotique. Nous avons pu montrer que le gène npc2d est issus d’une duplication et vraisemblablement d’une sub-fonctionnalisation et que les protéines NPC1 et NPC2 sont exprimées au voisinage des symbiotes. Nous proposons donc que la protéine NPC2-d soit utilisée comme marqueur de l’état de santé des Anthozoaires symbiotiques et que la protéine NPC1 soit un marqueur de la membrane périsymbiotique. Nous avons également développé un protocole afin d’identifier les protéines associées à l’interface symbiotique entre les deux partenaires. A terme, les cibles identifiées permettront une meilleure compréhension des mécanismes qui régulent la relation symbiotique.
https://tel.archives-ouvertes.fr/tel-01673491

NNT : 2015NICE4105
tel-01673491
https://tel.archives-ouvertes.fr/tel-01673491
https://tel.archives-ouvertes.fr/tel-01673491/document
https://tel.archives-ouvertes.fr/tel-01673491/file/2015NICE4105.pdf

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
BACKGROUND: Gastric cancer is one of the most common cancers in the world. The "economically developed countries" life style, including diet, constitutes a risk factor favoring this cancer. Diet modulation may lower digestive cancer incidence. Among promising food components, dairy propionibacteria were shown to trigger apoptosis of human colon cancer cells, via the release of short-chain fatty acids acetate and propionate. METHODOLOGY/PRINCIPAL FINDINGS: A fermented milk, exclusively fermented by P. freudenreichii, was recently designed. In this work, the pro-apoptotic potential of this new fermented milk was demonstrated on HGT-1 human gastric cancer cells. Fermented milk supernatant induced typical features of apoptosis including chromatin condensation, formation of apoptotic bodies, DNA laddering, cell cycle arrest and emergence of a subG1 population, phosphatidylserine exposure at the plasma membrane outer leaflet, reactive oxygen species accumulation, mitochondrial transmembrane potential disruption, caspase activation and cytochrome c release. Remarkably, this new fermented milk containing P. freudenreichii enhanced the cytotoxicity of camptothecin, a drug used in gastric cancer chemotherapy. CONCLUSIONS/SIGNIFICANCE: Such new probiotic fermented milk may thus be useful as part of a preventive diet designed to prevent gastric cancer and/or as a food supplement to potentiate cancer therapeutic treatments.
ISSN: 1932-6203

inserm-00871491
http://www.hal.inserm.fr/inserm-00871491
http://www.hal.inserm.fr/inserm-00871491/document
http://www.hal.inserm.fr/inserm-00871491/file/Milk_Fermented_by_Propionibacterium_freudenreichii.accepted.pdf
DOI : 10.1371/journal.pone.0031892

Éditeur(s) : HAL CCSD Elsevier
Résumé : Thanks to Dr M. Blanchard-Desce (UMR CNRS 5255, University of Bordeaux, France), who kindly provided us with fluorescent dye RS19 and the PIXEL, MRIc, flow cytometry and H2P2 platforms (SFR Biosit, UMS CNRS 3480/US INSERM 018, Rennes).
International audience
[1-9-NαC]-crourorb A1 is a cyclic peptide isolated from Croton urucurana Baillon latex, found in midwestern Brazil, that has been shown to exert cytotoxic effects against a panel of cancer cell lines. However, the underlying mechanisms responsible for the crourorb A1-induced cytotoxicity in cancer cells remain unknown. In this study, the effects of crourorb A1 on the viability, apoptosis, cell cycle and migration of Huh-7 (human hepatocarcinoma) cells were investigated. We evaluated the viability of Huh-7 cells treated with crourorb A1 in 2D and 3D collagen cultures and found that cells in 3D culture exhibited increased resistance to crourorb A1 compared to cells in 2D culture (IC50: 62μg/ml versus 35.75μg/ml). Crourorb A1 treatment decreases the viability of Huh-7 cells in a dose- and time-dependent manner and is associated with the induction of apoptosis, in the absence of necrotic cells, through the activation of caspase-3/7 and increased expression of the pro-apoptotic proteins Bak, Bid, Bax, Puma, Bim, and Bad. The effects of crourorb A1 are also associated with G2/M phase cell cycle arrest and increases in cyclin-dependent kinase (CDK1) and cyclin B1 expression. A significant reduction in Huh-7 cell migration induced by crourorb A1 was also observed in the presence of mitomycin C. Finally, we showed that the JNK/MAP pathway, but not ERK signaling, is involved in crourorb A1-induced hepatocarcinoma cell mortality.
ISSN: 0378-4274

hal-01526429
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526429
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526429/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01526429/file/de%20Matos%20C%C3%A2ndido-Bacani%20et%20al.%20-%20%5B1%E2%80%939-N%CE%B1C%5D-crourorb%20A1%20isolated%20from%20Croton%20urucura.pdf
DOI : 10.1016/j.toxlet.2017.03.020

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The mycotoxin enniatin B (EnnB) is predominantly produced by species of the Fusarium genera, and often found in grain. The cytotoxic effect of EnnB has been suggested to be related to its ability to form ionophores in cell membranes. The present study examines the effects of EnnB on cell death, differentiation, proliferation and pro-inflammatory responses in the murine monocyte-macrophage cell line RAW 264.7. Exposure to EnnB for 24 h caused an accumulation of cells in the G0/G1-phase with a corresponding decrease in cyclin D1. This cell cycle-arrest was possibly also linked to the reduced cellular ability to capture and internalize receptors as illustrated by the lipid marker ganglioside GM1. EnnB also increased the number of apoptotic, early apoptotic and necrotic cells, as well as cells with elongated spindle-like morphology. The Neutral Red assay indicated that EnnB induced lysosomal damage; supported by transmission electron microscopy (TEM) showing accumulation of lipids inside the lysosomes forming lamellar structures/myelin bodies. Enhanced levels of activated caspase-1 were observed after EnnB exposure and the caspase-1 specific inhibitor ZYVAD-FMK reduced EnnB-induced apoptosis. Moreover, EnnB increased the release of interleukin-1 beta (IL-1β) in cells primed with lipopolysaccharide (LPS), and this response was reduced by both ZYVAD-FMK and the cathepsin B inhibitor CA-074Me. In conclusion, EnnB was found to induce cell cycle arrest, cell death and inflammation. Caspase-1 appeared to be involved in the apoptosis and release of IL-1β and possibly activation of the inflammasome through lysosomal damage and leakage of cathepsin B.
ISSN: 0041-008X

inserm-00871698
http://www.hal.inserm.fr/inserm-00871698
DOI : 10.1016/j.taap.2012.03.014
PUBMED : 22483798

Éditeur(s) : HAL CCSD Cancer Research UK
Résumé : International audience
BACKGROUND: Cancer cell killing might be achieved by the combined use of available drugs. Statins are major anti-hypercholesterolemia drugs, which also trigger apoptosis of many cancer cell types, while docetaxel is a potent microtubule-stabilising agent. METHODS: Here, we looked at the combined effects of lovastatin and docetaxel in cancer cells. RESULTS: Whole transcriptome microarrays in HGT-1 gastric cancer cells demonstrated that lovastatin strongly suppressed expression of genes involved in cell division, while docetaxel had very little transcriptional effects. Both drugs triggered apoptosis, and their combination was more than additive. A marked rise in the cell-cycle inhibitor p21, together with reduction of aurora kinases A and B, cyclins B1 and D1 proteins was induced by lovastatin alone or in combination with docetaxel. The drug treatments induced the proteolytic cleavage of procaspase-3, a drop of the anti-apoptotic Mcl-1 protein, Poly-ADP-Ribose Polymerase and Bax. Strikingly, docetaxel-resistant HGT-1 cell derivatives overexpressing the MDR-1 gene were much more sensitive to lovastatin than docetaxel-sensitive cells. CONCLUSION: These results suggest that the association of lovastatin and docetaxel, or lovastatin alone, shows promise as plausible anticancer strategies, either as a direct therapeutic approach or following acquired P-glycoprotein-dependent resistance.
ISSN: 0007-0920

hal-00684528
https://hal.archives-ouvertes.fr/hal-00684528
DOI : 10.1038/bjc.2012.6
PUBMED : 22294184

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).
ISSN: 2045-2322

Droits : http://creativecommons.org/licenses/by/
hal-01359569
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569/file/The%20environmental%20carcinogen-CCBY%20%281%29.pdf
DOI : 10.1038/srep30776