Potentiating the efficacy of molecular targeted therapy for hepatocellular carcinoma by inhibiting the insulin-like growth factor pathway

• Published in: PloS one Vol. 8; no. 6; p. e66589
• Main Authors: Ou, Da-Liang, Lee, Bin-Shyun, Chang, Ya-Chi, Lin, Liang-In, Liou, Jun-Yang, Hsu, Chiun, Cheng, Ann-Lii
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.06.2013; Public Library of Science (PLoS)
• Subjects: Activation; AKT protein; Animals; Anticancer properties; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Biology; Blotting, Western; Cancer; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell growth; Cell Line, Tumor; Cell Survival - drug effects; Cells, Cultured; Checkpoint Kinase 2 - metabolism; Clinical trials; Cytotoxicity; Diabetes therapy; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Drug therapy; Enzyme inhibitors; Epidermal growth factor; Experiments; Gene expression; Health aspects; Hepatocellular carcinoma; Hospitals; Humans; Indoles - pharmacology; Inhibition; Insulin; Insulin-like growth factors; Internal medicine; Kinases; Laboratory animals; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Medicine; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Oncology; Phenylurea Compounds - pharmacology; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Proteins; Pyrimidines - pharmacology; Pyrroles - pharmacology; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Regulatory mechanisms (biology); Ribonucleic acid; RNA; RNA Interference; RNA-mediated interference; Signal transduction; Signal Transduction - drug effects; Signaling; Sorafenib; Sunitinib; Synergistic effect; Therapy; Tumorigenesis; Western blotting; Xenograft Model Antitumor Assays; Xenografts; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0066589

Insulin-like growth factor (IGF) signaling pathway is an important regulatory mechanism of tumorigenesis and drug resistance in many cancers. The present study explored the potential synergistic effects between IGF receptor (IGFR) inhibition and other molecular targeted agents (MTA) in HCC cells. HCC cell lines (Hep3B, PLC5, and SK-Hep1) and HUVECs were tested. The MTA tested included sorafenib, sunitinib, and the IGFR kinase inhibitor NVP-AEW541. The potential synergistic antitumor effects were tested by median dose effect analysis and apoptosis assay in vitro and by xenograft models in vivo. The activity and functional significance of pertinent signaling pathways and expression of apoptosis-related proteins were measured by RNA interference and Western blotting. We found that IGF can activate IGFR and downstream AKT signaling activities in all the HCC cells tested, but the growth-stimulating effect of IGF was most prominent in Hep3B cells. NVP-AEW541 can abrogate IGF-induced activation of IGFR and AKT signaling in HCC cells. IGF can increase the resistance of HCC cells to sunitinib. The apoptosis-inducing effects of sunitinib, but not sorafenib, were enhanced when IGFR signaling activity was inhibited by NVP-AEW541 or IGFR knockdown. Chk2 kinase activation was found contributory to the synergistic anti-tumor effects between sunitinib and IGFR inhibition. Our data indicate that the apoptosis-potentiating effects of IGFR inhibition for HCC may be drug-specific. Combination therapy of IGFR inhibitors with other MTA may improve the therapeutic efficacy in HCC.