Pre-clinical trial treatment of hepatocellular carcinoma on cirrhosis in a rat model
Zeybek Kuyucu, Ayça, author.

Pre-clinical trial treatment of hepatocellular carcinoma on cirrhosis in a rat model

Zeybek Kuyucu, Ayça, author.

Yazar Ek Girişi
Zeybek Kuyucu, Ayça, author.

Fiziksel Tanımlama
xiii, 102 leaves: illustrarions, charts;+ 1 computer laser optical disc.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer related 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 and migration with significantly higher potency than Sorafenib. Similarly, apoptotic cell was strongly increased 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 signaling 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. Key words: HCC, Sorafenib, AKT inhibitor, PI3K/AKT/mTOR pathway, target therapy, DEN, cirrhosis, rat, animal model.

Konu Başlığı
Liver -- Cancer.
Liver -- Cirrhosis.
Rats as laboratory animals.

Yazar Ek Girişi
Şanlı Mohamed, Gülşah,

Tüzel Kişi Ek Girişi
İzmir Institute of Technology. Biotechnology and Bioengineering.

Tek Biçim Eser Adı
Thesis (Doctoral)--İzmir Institute of Technology: Biotechnology and Bioengineering.
İzmir Institute of Technology: Biotechnology and Bioengineering--Thesis (Doctoral).

Elektronik Erişim
Access to Electronic Versiyon.

KütüphaneMateryal TürüDemirbaş NumarasıYer NumarasıDurumu/İade Tarihi
IYTETezT001578RC280.L5 Z63 2017Tez Koleksiyonu