III. Perspectives de développement de la fusicoccine A et de l’ophioboline A
2. Hémisynthèse de dérivés de la fusicoccine A et de l’ophioboline A
La fusicoccine A et l’ophioboline A, étant des molécules naturelles, ne peuvent pas être brevetées. C’est pourquoi nous envisageons, via une collaboration avec le Prof. A. Evidente, la synthèse d’hémidérivés de ces deux molécules. Dans le cas de la fusicoccine A, nous pourrions utiliser le docking moléculaire dont on a parlé précédemment pour orienter la synthèse de ces hémidérivés.
76
CONCLUSIONS
Au cours de ce travail, nous avons caractérisé l’activité anticancéreuse de la fusicoccine A et de l’ophioboline A mais également identifié, au moins en partie, leur mécanisme d’action. Nous nous sommes particulièrement intéressés aux glioblastomes qui sont associés à un pronostic très sombre de par leur caractère très invasif et leur résistance aux stimuli pro-apoptotique.
Tout d’abord, nos résultats ont révélé que l’activité inhibitrice de croissance in vitro de la fusicoccine A et de l’ophioboline A n’était pas dépendante du degré de sensibilité ou de résistance à l’apoptose des cellules gliales tumorales. Nous avons ensuite mis en évidence que la fusicoccine A diminuait l’invasion in vitro des cellules de glioblastome en ciblant la kinase d’adhérence focale (FAK). Par contre, nous avons montré que l’ophioboline A était capable d’induire la mort de ces cellules par paraptose en diminuant l’activité du canal ionique BKCa. La fusicoccine A et l’ophioboline A sont des agents chimiothérapeutiques potentiels pour le traitement du glioblastome car les cibles de ces deux molécules sont surexprimées dans les cellules de glioblastome et interviennent dans de nombreux processus cellulaires tels que la prolifération, la migration et la survie. Enfin, l’activité anti-tumorale in vivo de la fusicoccine A et de l’ophioboline A, dans des conditions non optimisées, a été évaluée sur un modèle murin de mélanome métastatique. Seule l’ophioboline A apportait un bénéfice thérapeutique
in vivo lorsqu’elle était administrée par voie intrapéritonéale à une concentration de 10 mg/kg. Lorsque nous aurons défini la formulation galénique adéquate, la dose maximale tolérée et le profil pharmacocinétique de ces deux molécules, nous testerons leur activité sur des modèles de xénogreffes orthotopiques de glioblastomes humains implantées dans le cerveau de souris immunodéficientes.
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