https://scholars.lib.ntu.edu.tw/handle/123456789/494610
Title: | Induction of Bim expression contributes to the antitumor synergy between sorafenib and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor CI-1040 in hepatocellular carcinoma | Authors: | DA-LIANG OU Ying-Chun Shen JA-DER LIANG Liou J.-Y. SUNG-LIANG YU Fan H.-H. Wang D.-S. YEN-SHEN LU CHIUN HSU ANN-LII CHENG |
Issue Date: | 2009 | Journal Volume: | 15 | Journal Issue: | 18 | Start page/Pages: | 5820-5828 | Source: | Clinical Cancer Research | Abstract: | Purpose: Sorafenib has proved survival benefit for patients with advanced hepatocellular carcinoma (HCC). This study explored whether the efficacy of sorafenib can be improved by adding the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor CI-1040 to vertically block the Raf/MEK/ERK pathway. Experimental Design: The growth inhibitory effects of sorafenib and CI-1040 were tested in HCC cell lines (Huh-7 and Hep3B) and human umbilical vascular endothelial cells (HUVEC). The potential synergistic growth inhibitory effects were measured by median effect analysis. Apoptosis was measured by flow cytometry. The effects on ERK phosphorylation and levels of apoptosis regulatory proteins were measured by Western blotting. The in vivo antitumor activity of sorafenib and CI-1040 were tested in xenograft HCC models. Results: Combination of sorafenib and CI-1040 synergistically inhibited ERK phosphorylation and cell growth and induced apoptosis in both HCC cells and HUVECs. Increased expression of Bim protein, which correlated with the extent of ERK inhibition, was found in both HCC cells and HUVECs. Knockdown of Bim expression by small interfering RNA partially abrogated the synergistic proapoptotic effects of sorafenib and CI-1040. Combination therapy inhibited tumor growth significantly better than either single agent in the xenograft models. Conclusion: The antitumor effects of sorafenib in HCC can be improved by vertical blockade of Raf/MEK/ERK signaling with CI-1040. ? 2009 American Association for Cancer Research. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-70349452270&doi=10.1158%2f1078-0432.CCR-08-3294&partnerID=40&md5=48e4e34767bdb1c218b2bdad7987bffb https://scholars.lib.ntu.edu.tw/handle/123456789/494610 |
ISSN: | 1078-0432 | DOI: | 10.1158/1078-0432.CCR-08-3294 | SDG/Keyword: | 2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3,4 difluorobenzamide; BIM protein; mitogen activated protein kinase; Raf protein; small interfering RNA; sorafenib; animal experiment; animal model; animal tissue; apoptosis; article; cancer cell destruction; cancer combination chemotherapy; cancer growth; cancer inhibition; cancer model; controlled study; drug efficacy; drug potentiation; endothelium cell; enzyme inactivation; enzyme inhibition; enzyme phosphorylation; flow cytometry; gene expression regulation; gene induction; gene silencing; human; human cell; in vivo study; liver cell carcinoma; monotherapy; mouse; nonhuman; pharmacogenetics; priority journal; signal transduction; tumor growth; umbilical vein; vascular endothelium; Western blotting; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Benzamides; Benzenesulfonates; Carcinoma, Hepatocellular; Cell Survival; Drug Screening Assays, Antitumor; Drug Synergism; Endothelial Cells; Extracellular Signal-Regulated MAP Kinases; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Membrane Proteins; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Proto-Oncogene Proteins; Pyridines; raf Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Tumor Cells, Cultured |
Appears in Collections: | 醫學院附設醫院 (臺大醫院) |
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