Please use this identifier to cite or link to this item: https://hdl.handle.net/11147/5693
Title: Pre-clinical trial treatment of hepatocellular carcinoma on cirrhosis in a rat model
Other Titles: Sirotik sıçan modellerinde hepatosellüler karsinomun klinik öncesi tedavisi
Authors: Şanlı Mohamed, Gülşah
Zeybek Kuyucu, Ayça
Zeybek Kuyucu, Ayça
Keywords: Hepatocellular carcinoma
Sorafenib
AKT inhibitor
Target therapy
Cirrhosis
Rat
Animal model
Issue Date: Jan-2017
Publisher: İzmir Institute of Technology
Izmir Institute of Technology
Source: Zeybek Kuyucu, A. (2017). Pre-clinical trial treatment of hepatocellular carcinoma on cirrhosis in a rat model. Unpublished doctoral dissertation, İzmir Institute of Technology, İzmir, Turkey
Abstract: 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.
Hepatosellüler karsinom (HSK) dünyada en çok görülen kanser türleri arasında beşinci sıklıkta, mortalitesi ise ikinci sıklıkta yer almaktadır. HSK durumlarında AKT yolağı %50 oranında artış göstermektedir. Bu yüzden, yeni sentezlenmiş Allosterik AKT inhibitörleri ve aynı zamanda bu inhibitörler ile Sorafenib molekülün kimbinasyonlu hali hem HSK hücre hatlarındaki hem de sirotik sıçanlardaki etkileri incelenmiştir. In vitro çalışmalarında, AKT inhibitötlerinin AKT’nin fosforillenmesini bloke edip, hücre büyümesinin ve hücre göçünün Srafenib’e kıyasla önemli ölçüde azalttığı bulunmuştur. Benzer şekilde, apoptotik hücrelerin arttığı gözlenmiştir. In vivo çalışmalarında, insanda ilerlemiş HSK’ya en yakın model oluşturmak için sıçanlara dietilnitrozamin (DEN) enjekte edildi. MRI analizine göre tümör ilerlemesi anlamlı ölçüde hem AKT inhibitör gurubunda hem de kombinasyonlu grupta kontrole göre, sadece kombinasyonlu grupta Sorafenib’e göre anlamlı ölçüde azalma olmuştur. Patolojik analiz de de anlamlı ölçüde tümör sayısında ve tümör boyutunda azalma gözlenmiştir. Üstelik yapılan immünohistokimya deneylerin de apoptozu arttırdığı hücre çoğalmasının anlamlı ölçüde azaldığı bulunmuştur. Son olarak, pAKT/AKT oranının ciddi oranda ARQ 092 gurubunda azaldığı gözlenmiştir.
Description: Thesis (Doctoral)--İzmir Institute of Technology, Bioengineering, İzmir, 2017
Includes bibliographical references (leaves. 88-98)
Text in English; Abstract: Turkish and English
xiii, 102 leaves
URI: http://hdl.handle.net/11147/5693
Appears in Collections:Phd Degree / Doktora

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