Back to Search
Start Over
Inhibition of the Wnt/β-catenin signaling pathway improves the anti-tumor effects of sorafenib against hepatocellular carcinoma.
- Source :
-
Cancer Letters . Oct2016, Vol. 381 Issue 1, p58-66. 9p. - Publication Year :
- 2016
-
Abstract
- Sorafenib, a multikinase inhibitor, is currently the only approved drug for advanced hepatocellular carcinoma (HCC). The current study tested the hypothesis whether inhibition of the Wnt/β-catenin signaling pathway could improve the anti-tumor effects of sorafenib in HCC. ICG-001, a small molecule which blocks the interaction of β-catenin with its transcriptional coactivator CBP, dose-dependently enhanced the growth-suppressive and apoptosis-induction effects of sorafenib in multiple HCC cell lines. Downregulation of β-catenin by RNA interference increased sorafenib sensitivity, whereas overexpression of β-catenin reduced sorafenib sensitivity in Huh7 cells. The sorafenib-sensitization effect of short hairpin RNA (shRNA)-mediated β-catenin downregulation in Huh7 cells was attenuated by β-catenin overexpression. Mechanistically, sorafenib combined with ICG-001 or shRNA-mediated β-catenin downregulation augmented the induction of apoptosis, and resulted in a significant downregulation of Mcl-1 in HCC cells. In Huh7 cell mouse xenograft model, the combination of ICG-001 and sorafenib showed a more significant growth-retarding effect than single agent treatment of sorafenib or ICG-001. Our data indicate that inhibition of the Wnt/β-catenin signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo. [ABSTRACT FROM AUTHOR]
- Subjects :
- *LIVER cancer
*CELLULAR signal transduction
*CATENINS
*SORAFENIB
*GENETIC overexpression
*TUMOR treatment
*PROTEIN metabolism
*ANIMAL experimentation
*ANIMALS
*ANTINEOPLASTIC agents
*APOPTOSIS
*CELL physiology
*CYTOSKELETAL proteins
*DOSE-effect relationship in pharmacology
*EPITHELIAL cells
*GENES
*GENETIC techniques
*HEPATOCELLULAR carcinoma
*HETEROCYCLIC compounds
*LIVER tumors
*MICE
*UREA
*VITAMIN B complex
*PROTEIN kinase inhibitors
*PHARMACODYNAMICS
*THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 03043835
- Volume :
- 381
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Cancer Letters
- Publication Type :
- Academic Journal
- Accession number :
- 117893575
- Full Text :
- https://doi.org/10.1016/j.canlet.2016.07.013