https://scholars.lib.ntu.edu.tw/handle/123456789/502684
Title: | Vertical blockade of the IGFR- PI3K/Akt/mTOR pathway for the treatment of hepatocellular carcinoma: The role of survivin | Authors: | DA-LIANG OU Lee B.-S. LIANG-IN LIN Liou J.-Y. Liao S.-C. CHIUN HSU ANN-LII CHENG |
Issue Date: | 2014 | Journal Volume: | 13 | Journal Issue: | 1 | Start page/Pages: | 2 | Source: | Molecular Cancer | Abstract: | Background: To 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).Methods: HCC 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.Results: Vertical 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.Conclusions: Vertical 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. ? 2014 Ou et al.; licensee BioMed Central Ltd. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/502684 | ISSN: | 1476-4598 | DOI: | 10.1186/1476-4598-13-2 | SDG/Keyword: | 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; dactolisib; everolimus; mammalian target of rapamycin; nvp aew 541; phosphatidylinositol 3 kinase; protein kinase B; somatomedin receptor; survivin; animal experiment; animal model; antineoplastic activity; apoptosis; article; cancer cell culture; controlled study; dose response; drug efficacy; drug potentiation; enzyme inhibition; flow cytometry; gene overexpression; gene silencing; human; human cell; in vitro study; liver cell carcinoma; male; mediator; molecularly targeted therapy; mouse; nonhuman; protein expression; tumor xenograft; umbilical vein endothelial cell; Western blotting; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Drug Synergism; Enzyme Inhibitors; Flow Cytometry; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Liver Neoplasms; Male; Mice, Inbred BALB C; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrimidines; Pyrroles; Quinolines; Receptors, Somatomedin; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Markers, Biological; Xenograft Model Antitumor Assays |
Appears in Collections: | 醫學檢驗暨生物技術學系 |
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