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, lignées cancéreuses est aussi un marqueur d'un rendement énergétique (production d'ATP) plus faible alors même que le flux glycolytique est plus prononcé

. Da-veiga-moreira, Metabolic therapies inhibit tumor growth in vivo and in silico, 2019.

, Dans le chapitre précédent nous avons présenté des résultats en concordance avec les hypothèses de Warburg sur le caractère fermentaire du métabolisme des cellules cancéreuses comparées aux cellules saines qui, elles, privilégient l'oxydation phosphorylative (OxPhos) pour la production d'énergie. Des pistes d'interventions thérapeutiques ont été proposées afin d

. Dans, Il s'agit de l'acide ?-lipoïque et de l'hydroxycitrate, tous deux utilisés comme compléments alimentaires et activateur de la pyruvate déshydrogénase (PDH) et de l'ATPcitrate lyase (ACL), respectivement, la metformine est un glucophase utilisée dans le diabète de type II et activateur du complexe I et enfin le diclofénac qui est un anti-inflammatoire et, nous présentons des résultats de recherche sur des souris auxquelles des tumeurs ont été greffées et soumises à des traitements métaboliques pendant 59 jours

, Un groupe « contrôle » de souris a été traité au cisplatine, un agent chimio-thérapeutique classique

, Les résultats montrent que la combinaison de ces quatre molécules a un effet inhibiteur sur la croissance de la tumeur implantée aux souris. En effet, lorsque les molécules sont utilisées séparément, elles ne montrent pas d'effets majeurs comparés à la chimiothérapie. Cependant lorsque la metformine est appliquée à haute dose en complément de l'acide ?-lipoïque et de l'hydroxycitrate

, jours de suivi (cf. Fig. 2b de l'article). L'inhibition est encore plus marquée lorsque le diclofénac à haute dose est ajouté à la thérapie (cf. Fig

, Ce modèle comprend des voies métaboliques réduites et simplifiées du métabolisme des cellules cancéreuses et parvient à simuler la croissance de la tumeur mais aussi l'effet inhibiteur de la thérapie métabolique obtenu expérimentalement (cf. Fig. 4 de l'article). Les simulations montrent une inversion de l'effet Warburg sous l'action des molécules. Cela est mise en évidence par un flux net de re, Un modèle cinétique du MCC a été développé pour simuler la croissance de la tumeur et prédire l'effet des molécules précédentes sur les flux énergétiques intracellulaires

, de la respiration mitochondriale (cf. Fig. 5 de l'article), un phenotype caractéristique des

, Les données présentées ici (Fig. 19abc) sont des résultats préliminaires issus d'une seule série d'expériences. Des essais supplémentaires seront réalisés afin de valider ces premiers résultats

, Différentes concentrations en sels citrate (NaCit et CaCit) ont été utilisées dans cette étude expérimentale par variation autour de la concentration physiologique en citrate de 100 µM

, Parmi les deux sels de citrate ajoutés aux cultures, seule la forme de citrate complexée au calcium semble avoir un effet positif sur la synthèse du collagène. L'ajout du CaCit à 200 µM semble stimuler la synthèse du collagène de manière significative (Fig. 1C). La forme NaCit du citrate ne montre aucun effet majeur du citrate par rapport aux contrôles

, Ces résultats semblent confirmer l'hypothèse communément acceptée indiquant que le calcium est capté par les ostéoblastes en symport avec le citrate. Bien que l'effet du calcium seul (CaCl2), par rapport au citrate, ne montre pas d'effet significatif, le citrate pourrait avoir un effet indirect sur la stimulation de la différenciation des ostéoblastes et donc de sur synthèse du collagène

, Figure 19 : L'effet des sels de citrate sur la synthèse du collagène par les ostéoblastes, p.206

, µM) sur la différenciation des cellules primaires osseuses de souris. Le citrate semble potentialiser les effets du calcium sur la differentiation des ostéoblastes. Ces expériences doivent être répétées, notamment à des concentrations en citrate plus importantes. En termes d'application directe de ces résultats, il est aussi envisageable d'étudier in vivo les effets d'une matrice alimentaire enrichie en citrate sur la santé de l'os chez des modèles de souris ovariectomisées, Conclusion Les résultats présentés ici sont issus d'expériences préliminaires et montrent un effet stimulant du citrate de calcium (CaCit) à haute dose, p.207

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, Ces résultats ont été obtenus sur des cultures de Y. lipolytica W29 en conditions non-optimales, en fioles agitées

. Akimenko, AOX est impliquée dans la respiration alternative chez Yarrowia lipolytica mais aussi chez des plantes et certains champignons, 2003.

. Medentsev, La propyl gallate est un antioxydant (E310) utilisé depuis de nombreuses années dans les industries agro-alimentaires et pharma-cosmétiques. C'est une molécule reconnue GRAS (Generally Recognized as Safe) par la FDA (Food and Drug Administration) américaine et utilisée comme conservateur dans les produits alimentaires à base d'huile, International Journal of Toxicology, 2002.

, et en particulier chez des microorganismes dotés de mitochondries et d'un métabolisme oxydatif, les principales sources d'espèces ROS. Le métabolisme mitochondrial de l'oxygène semble être impliqué dans la transition respirofermentaire de par la contrainte métabolique que l'O2 impose aux flux d'électrons qui parcourent la chaîne respiratoire. Ainsi une inhibition de la consommation de l'oxygène par la nPG peut expliquer une saturation électro-chimique des électrons au niveau de la chaîne de transfert des électrons et une diminution des flux, Ces résultats suggèrent l'importance l'importance du contrôle de l'état rédox du milieu intracellulaire chez toutes les cellules

, La production d'acides organiques issus du Krebs dont majoritairement le citrate pourrait s'expliquer par cette limitation du flux oxytatif et constituerait alors une « issue de secours

. Ochoa-estopier, Ces observations ont justifié la nécessité d'utiliser des approches informatiques pour l'étude du métabolisme de Y. lipolytica afin d'identifier les potentiels points de bascule métabolique et leviers dans l'optique d'une optimisation de la production de citrate. La méthode dynamic FBA (Flux Balance Analysis) nous a permis de modéliser le métabolisme de Y. lipolytica à l'échelle du genome. L'analyse des flux à mis en evidence des mechanismes intracellulaires pouvant expliquer l'accumulation de citrate dans une culture de Y. lipolytica ainsi qu'une surproduction par l'application de la nPG. Les simulations de l'inhibition de l'AOX par la nPG semble augmenter le flux d'oxydation des lipides et une accumulation des expèces ROS. Nos résultats expérimentaux préliminaires tendent à valider ces simulations puisqu'il a été observé que l'ajout de la nPG dans une culture de Y. lipolytica favorise non seulement une surproduction de citrate mais aussi une accumulation de corps cétoniques issues de la dégradation de triglycérides, De plus ces résultats confirment certaines observations reportées dans la littérature scientifique décrivant l'accumulation de citrate dans le milieu de culture comme la conséquence d'un overflow métabolique et/ou transition métabolique décorélée de l'expression des gènes. Ainsi, les données transcriptomiques n'ont montré que très peu de différences au niveau de l'expression des enzymes impliquées dans les voies métaboliques favorisant l'accumulation de citrate, 2014.

, En perspectives, on pourrait bien imaginer l'intégration d'un système de respiration alternative chez certaines cellules animales. Cela contribuerait à apporter un degré de liberté supplémentaire aux cellules dans le recyclage des espèces NAD + /NADH et une diminution du phénotype fermentaire

V. K. Références-akimenko, A. Y. Arinbasarova, N. M. Smirnova, and A. G. Medentsev, The Alternative Oxidase of Yarrowia lipolytica Mitochondria Is Unable To Compete with the Cytochrome Pathway for Electrons, Microbiology, vol.72, pp.403-407, 2003.

S. Guerrero-castillo, A. Cabrera-orefice, M. Vázquez-acevedo, D. González-halphen, and S. Uribe-carvajal, During the stationary growth phase, Yarrowia lipolytica prevents the overproduction of reactive oxygen species by activating an uncoupled mitochondrial respiratory pathway, Biochim. Biophys. Acta, vol.1817, pp.353-362, 2012.

, Final Report on the Amended Safety Assessment of Propyl Gallate1, 2007.

A. G. Medentsev, A. Y. Arinbasarova, N. P. Golovchenko, and V. K. Akimenko, Involvement of the alternative oxidase in respiration of Yarrowia lipolytica mitochondria is controlled by the activity of the cytochrome pathway, FEMS Yeast Res, vol.2, pp.519-524, 2002.