Potentiating the Efficacy of Molecular Targeted Therapy for Hepatocellular Carcinoma by Inhibiting the Insulin-Like Growth Factor Pathway
Journal
PLoS ONE
Journal Volume
8
Journal Issue
6
Pages
e66589
Date Issued
2013
Author(s)
Abstract
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. ? 2013 Ou et al.
SDGs
Other Subjects
checkpoint kinase 2; nvp aew 541; protein kinase B; somatomedin; somatomedin receptor; sorafenib; sunitinib; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; article; cancer resistance; concentration response; controlled study; drug efficacy; drug potentiation; enzyme activation; gene silencing; human; human cell; in vitro study; in vivo study; liver cell carcinoma; male; molecularly targeted therapy; mouse; nonhuman; protein expression; RNA interference; signal transduction; tumor xenograft; umbilical vein endothelial cell; Western blotting; Animals; Antineoplastic Agents; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Cells, Cultured; Checkpoint Kinase 2; Drug Resistance, Neoplasm; Drug Synergism; Humans; Indoles; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Niacinamide; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Receptor, IGF Type 1; RNA Interference; Signal Transduction; Xenograft Model Antitumor Assays
Type
journal article