Abstract
Purpose: RAD001 targets at the mammalian target of rapamycin (mTOR), while TKI-258 is a potent tyrosine kinase inhibitor targeting at fibroblast growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor and c-kit. We aim to study the activity of combined RAD001 and TKI-258 in cell lines and xenograft model of hepatocellular carcinoma (HCC), with reference to the parallel and upstream pathways of Akt-mTOR axis. Methods: A panel of 4 human HCC cell lines HepG2, Hep3B, PLC/PRF/5 and Huh7 and the Hep3B-derived xenograft were treated with TKI-258 or/and RAD001, respectively. Related mechanistic studies (including apoptosis and angiogenesis) were conducted. Results: There was an enhanced increase in suppression of cell proliferation with combined TKI-258 and RAD001 compared with either drug alone. The combination could significantly suppress the phosphorylation of mTOR, MEK1/2 and p38 MAPK. Although the addition of the TKI258 only slightly suppressed the phosphorylation of AKT induced by RAD001, the pi-mTOR and its downstream signaling pathways including pi-p70S6K, pi-S6 and pi-4EBP1 were lowered in the combination. In Hep3B-derived xenograft, TKI-258 and RAD001 had shown an enhanced inhibition of tumor growth without impact on the weight of animals. There was a reduction in microvessel density in the xenograft with the combination, which indicated an enhanced inhibition on angiogenesis. Pro-caspases-3 and PARP cleavage were slightly detected at 48 h after treatment, suggesting that the combination mainly increased the cytostatic arrest ability. Conclusions: The combination of RAD001 and TKI-258 was active in HCC via inhibition of both mTOR-mediated signaling and its parallel pathways.
Original language | English (US) |
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Pages (from-to) | 1417-1425 |
Number of pages | 9 |
Journal | Cancer Chemotherapy and Pharmacology |
Volume | 71 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2013 |
Externally published | Yes |
Keywords
- AKT
- Hepatocellular carcinoma
- mTOR
- RAD001
- TKI-258
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)