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01.06.2013 | Original Article

Preclinical evaluation of combined TKI-258 and RAD001 in hepatocellular carcinoma

verfasst von: Stephen L. Chan, Chi-Hang Wong, Cecilia P. Y. Lau, Qian Zhou, Connie W. C. Hui, Vivian W. Y. Lui, Brigette B. Y. Ma, Anthony T. C. Chan, Winnie Yeo

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2013

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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.

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Titel: Preclinical evaluation of combined TKI-258 and RAD001 in hepatocellular carcinoma
verfasst von: Stephen L. Chan
Chi-Hang Wong
Cecilia P. Y. Lau
Qian Zhou
Connie W. C. Hui
Vivian W. Y. Lui
Brigette B. Y. Ma
Anthony T. C. Chan
Winnie Yeo
Publikationsdatum: 01.06.2013
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2013
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2139-4

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