Vertical blockade of the IGFR- PI3K/Akt/mTOR pathway for the treatment of hepatocellular carcinoma: the role of survivin

Molecular Cancer

Research

Liang-In Lin¹  Chiun Hsu²  Ann-Lii Cheng³  Da-Liang Ou⁴  Jun-Yang Liou⁵  Bin-Shyun Lee⁶  Sheng-Chieh Liao⁶ 

[1]Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan

[2]Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan

[3]Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, 100, Taipei, Taiwan

[4]Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

[5]Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan

[6]Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, 100, Taipei, Taiwan

[7]Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

[8]Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

[9]Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan

[10]National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan

[11]Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan

[12]National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan

[13]Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, 100, Taipei, Taiwan

关键词: Molecular targeted therapy;    Insulin-like growth factor;    NVP-AEW541;    MK2206;    BEZ235;    RAD001;   

DOI  :  10.1186/1476-4598-13-2

 received in 2013-08-28, accepted in 2013-12-27,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundTo explore whether combining inhibitors that target the insulin-like growth factor receptor (IGFR)/PI3K/Akt/mTOR signaling pathway (vertical blockade) can improve treatment efficacy for hepatocellular carcinoma (HCC).MethodsHCC cell lines (including Hep3B, Huh7, and PLC5) and HUVECs (human umbilical venous endothelial cells) were tested. The molecular targeting therapy agents tested included NVP-AEW541 (IGFR kinase inhibitor), MK2206 (Akt inhibitor), BEZ235 (PI3K/mTOR inhibitor), and RAD001 (mTOR inhibitor). Potential synergistic antitumor effects were tested by median dose-effect analysis in vitro and by xenograft HCC models. Apoptosis was analyzed by flow cytometry (sub-G1 fraction analysis) and Western blotting. The activities of pertinent signaling pathways and expression of apoptosis-related proteins were measured by Western blotting.ResultsVertical blockade induced a more sustained inhibition of PI3K/Akt/mTOR signaling activities in all the HCC cells and HUVEC tested. Synergistic apoptosis-inducing effects, however, varied among different cell lines and drug combinations and were most prominent when NVP-AEW541 was combined with MK2206. Using an apoptosis array, we identified survivin as a potential downstream mediator. Over-expression of survivin in HCC cells abolished the anti-tumor synergy between NVP-AEW541 and MK2206, whereas knockdown of survivin improved the anti-tumor effects of all drug combinations tested. In vivo by xenograft studies confirmed the anti-tumor synergy between NVP-AEW541 and MK2206 and exhibited acceptable toxicity profiles.ConclusionsVertical blockade of the IGFR/PI3K/Akt/mTOR pathway has promising anti-tumor activity for HCC. Survivin expression may serve as a biomarker to predict treatment efficacy.

【 授权许可】

Unknown   
© Ou et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.