Essai du traitement pré-clinique du carcinome hépatocellulaire sur la cirrhose dans le modèle de rat / Ayça Zeybek ; sous la direction de Patrice Marche

Date :

Type : Livre / Book

Type : Thèse / Thesis

Langue / Language : anglais / English

Carcinome hépatocellulaire

Rats de laboratoire

Cirrhose hépatique

Classification Dewey : 540

Marche, Patrice (19..-....) (Directeur de thèse / thesis advisor)

Özçelik, Serdar (19..-....) (Président du jury de soutenance / praeses)

Öztürk, Mehmet (Rapporteur de la thèse / thesis reporter)

Şanlier, Şenay (19..-....) (Rapporteur de la thèse / thesis reporter)

Lerat, Hervé (19..-.... ; auteur en médecine) (Rapporteur de la thèse / thesis reporter)

Decaens, Thomas (1974-.... ; hépato-gastro-entérologue) (Membre du jury / opponent)

Şanli Mohamed, Gülşah (19..-....) (Membre du jury / opponent)

Atabey, Neşe Safiye (19..-....) (Membre du jury / opponent)

Communauté d'universités et d'établissements Université Grenoble Alpes (2015-2019) (Organisme de soutenance / degree-grantor)

İzmir Yüksek Teknoloji Enstitüsü (Izmir, Turquie) (Organisme de cotutelle / degree co-grantor)

École doctorale chimie et science du vivant (Grenoble ; 199.-....) (Ecole doctorale associée à la thèse / doctoral school)

Institut Albert Bonniot (Grenoble, Isère, France ; 2007-2015) (Laboratoire associé à la thèse / thesis associated laboratory)

Résumé / Abstract : Hepatocellular carcinoma (HCC) is the second most common cause of cancerrelated mortality worldwide. AKT pathway has been found activated in 50% of HCC cases, making it promising target. Therefore we assess efficacy of the allosteric AKT inhibitor or the combination of Sorafenib with AKT inhibitor compared to untreated control and to standard treatment, Sorafenib, in vitro and in vivo. AKT inhibitor blocked phosphorylation of AKT in vitro and strongly inhibited cell growth with significantly higher potency than Sorafenib. Similarly, apoptosis and cell migration were strongly reduced by AKT inhibitor in vitro. To mimic human advanced HCC, we used diethylnitrosamine-induced cirrhotic rat model with fully developed HCC. MRI analyses showed that AKT inhibitor significantly reduced overall tumor size. Furthermore, number of tumors was decreased by AKT inhibitor, which was associated with increased apoptosis and decreased proliferation. Tumor contrast enhancement was significantly decreased in the AKT inhibitor group. Moreover, on tumor tissue sections, we observed a vascular normalization and a significant decrease in fibrosis in surrounding liver of animals treated with AKT inhibitor. Finally, pAKT/AKT levels in AKT inhibitor treated tumors were reduced, followed by down regulation of actors of AKT downstream signalling pathway: pmTOR, pPRAS40, pPLCγ1 and pS6K1. In conclusion, we demonstrated that AKT inhibitor blocks AKT phosphorylation in vitro and in vivo. In HCC-rat model, AKT inhibitor was well tolerated, showed anti-fibrotic effect and had stronger antitumor effect than Sorafenib. Our results confirm the importance of targeting AKT in HCC.

Résumé / Abstract : Hepatocellular carcinoma (HCC) is the second most common cause of cancerrelated mortality worldwide. AKT pathway has been found activated in 50% of HCC cases, making it promising target. Therefore we assess efficacy of the allosteric AKT inhibitor or the combination of Sorafenib with AKT inhibitor compared to untreated control and to standard treatment, Sorafenib, in vitro and in vivo. AKT inhibitor blocked phosphorylation of AKT in vitro and strongly inhibited cell growth with significantly higher potency than Sorafenib. Similarly, apoptosis and cell migration were strongly reduced by AKT inhibitor in vitro. To mimic human advanced HCC, we used diethylnitrosamine-induced cirrhotic rat model with fully developed HCC. MRI analyses showed that AKT inhibitor significantly reduced overall tumor size. Furthermore, number of tumors was decreased by AKT inhibitor, which was associated with increased apoptosis and decreased proliferation. Tumor contrast enhancement was significantly decreased in the AKT inhibitor group. Moreover, on tumor tissue sections, we observed a vascular normalization and a significant decrease in fibrosis in surrounding liver of animals treated with AKT inhibitor. Finally, pAKT/AKT levels in AKT inhibitor treated tumors were reduced, followed by down regulation of actors of AKT downstream signalling pathway: pmTOR, pPRAS40, pPLCγ1 and pS6K1. In conclusion, we demonstrated that AKT inhibitor blocks AKT phosphorylation in vitro and in vivo. In HCC-rat model, AKT inhibitor was well tolerated, showed anti-fibrotic effect and had stronger antitumor effect than Sorafenib. Our results confirm the importance of targeting AKT in HCC.