Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis
- Equal contributors
1 Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
2 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People’s Republic of China
3 Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, 49503, USA
4 Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, 6767 Bertner Ave., Unit 1002, BSRB S5.8116, Houston, TX, 77030, USA
5 Department of Hepatobilliary Surgery, 1st Affiliated Hospital to Guangzhou University of Chinese Medicine, 16 Jichang Road, Guangzhou, 510405, China
Journal of Translational Medicine 2012, 10:245 doi:10.1186/1479-5876-10-245Published: 10 December 2012
Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor β. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC).
In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib.
Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-β was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-β, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 μmol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells.
Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.