File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

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

TitlePreclinical evaluation of combined TKI-258 and RAD001 in hepatocellular carcinoma
Authors
Issue Date2013
Citation
Cancer Chemotherapy and Pharmacology, 2013, v. 71 n. 6, p. 1417-1425 How to Cite?
AbstractPurpose: 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. © 2013 Springer-Verlag Berlin Heidelberg.
Persistent Identifierhttp://hdl.handle.net/10722/194398
ISSN
2015 Impact Factor: 2.824
2015 SCImago Journal Rankings: 1.283
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChan, SL-
dc.contributor.authorWong, C-H-
dc.contributor.authorLau, CPY-
dc.contributor.authorZhou, Q-
dc.contributor.authorHui, CWC-
dc.contributor.authorLui, VWY-
dc.contributor.authorMa, BBY-
dc.contributor.authorChan, ATC-
dc.contributor.authorYeo, W-
dc.date.accessioned2014-01-30T03:32:32Z-
dc.date.available2014-01-30T03:32:32Z-
dc.date.issued2013-
dc.identifier.citationCancer Chemotherapy and Pharmacology, 2013, v. 71 n. 6, p. 1417-1425-
dc.identifier.issn0344-5704-
dc.identifier.urihttp://hdl.handle.net/10722/194398-
dc.description.abstractPurpose: 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. © 2013 Springer-Verlag Berlin Heidelberg.-
dc.languageeng-
dc.relation.ispartofCancer Chemotherapy and Pharmacology-
dc.titlePreclinical evaluation of combined TKI-258 and RAD001 in hepatocellular carcinoma-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1007/s00280-013-2139-4-
dc.identifier.pmid23546591-
dc.identifier.scopuseid_2-s2.0-84878635090-
dc.identifier.volume71-
dc.identifier.issue6-
dc.identifier.spage1417-
dc.identifier.epage1425-
dc.identifier.isiWOS:000319751400004-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats