PMID- 19220580
OWN - NLM
STAT- MEDLINE
DCOM- 20100719
LR  - 20220316
IS  - 1582-4934 (Electronic)
IS  - 1582-1838 (Print)
IS  - 1582-1838 (Linking)
VI  - 13
IP  - 8B
DP  - 2009 Aug
TI  - Sorafenib and rapamycin induce growth suppression in mouse models of 
      hepatocellular carcinoma.
PG  - 2673-2683
LID - 10.1111/j.1582-4934.2009.00692.x [doi]
AB  - Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. 
      Vascular endothelial growth factor, platelet derived growth factor and the 
      Raf/mitogen-activated protein kinase/extracellular signal regulated kinase 
      (Raf/MEK/ERK) signalling pathway regulates the growth, neovascularization, 
      invasiveness and metastatic potential of HCC. In this study, we investigated the 
      in vivo antitumour activity and mechanisms of action of sorafenib tosylate on 
      four patient-derived HCC xenografts. Sorafenib dosed at 50 mg/kg and 100 mg/kg 
      inhibited tumour growth by 85% and 96%, respectively. Sorafenib-induced growth 
      suppression and apoptosis were associated with inhibition of angiogenesis, 
      down-regulation of phospho-platelet-derived growth factor receptor beta Tyr1021, 
      phospho-eIF4E Ser209, phospho-c-Raf Ser259, c-Raf, Mcl-1, Bcl-2, Bcl-x and 
      positive cell cycle regulators, up-regulation of apoptosis signalling kinase-1, 
      p27 and p21. Expression of IGF-1Rbeta and phosphorylation of c-Raf Ser338, MEK1/2 
      Ser217/221 and ERK1/2 Thr202/Tyr204 were increased by sorafenib treatment. 
      Phosphorylation of mammalian target-of-rapamycin (mTOR) targets (p70S6K, S6R and 
      4EBP1) was reduced by sorafenib in sorafenib-sensitive lines but activated in 
      sorafenib-less-sensitive 10-0505 xenograft. Sorafenib-induced phosphorylation of 
      c-met, p70S6K and 4EBP1 was significantly reduced when 10-0505 cells were 
      co-treated with anti-human anti-HGF antibody, suggesting that treatment with 
      sorafenib leads to increased HGF secretion and activation of c-met and mTOR 
      targets. Treatment of 10-0505 tumours with sorafenib plus rapamycin resulted in 
      growth inhibition, inhibition of vascular endothelial growth factor receptor-2 
      phosphorylation, increased apoptosis and completely blocked sorafenib-induced 
      phosphorylation of mTOR targets and cyclin B1 expression. These data also provide 
      a strong rationale for clinical investigation of sorafenib in combination with 
      mTOR inhibitors in patients with HCC.
FAU - Huynh, Hung
AU  - Huynh H
AD  - Laboratory of Molecular Endocrinology, Division of Molecular and Cellular 
      Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 
      Singapore.
FAU - Ngo, Van Chanh
AU  - Ngo VC
AD  - Laboratory of Molecular Endocrinology, Division of Molecular and Cellular 
      Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 
      Singapore.
FAU - Koong, Heng Nung
AU  - Koong HN
AD  - Department of Surgical Oncology, Humphrey Oei Institute of Cancer Research, 
      National Cancer Centre, Singapore.
FAU - Poon, Donald
AU  - Poon D
AD  - Department of Surgical Oncology, Humphrey Oei Institute of Cancer Research, 
      National Cancer Centre, Singapore.
FAU - Choo, Su Pin
AU  - Choo SP
AD  - Department of Surgical Oncology, Humphrey Oei Institute of Cancer Research, 
      National Cancer Centre, Singapore.
FAU - Thng, Choon Hua
AU  - Thng CH
AD  - Department of Oncologic Imaging, Humphrey Oei Institute of Cancer Research, 
      National Cancer Centre, Singapore.
FAU - Chow, Pierce
AU  - Chow P
AD  - Department of General Surgery, Singapore General Hospital, Singapore.
FAU - Ong, Hock Soo
AU  - Ong HS
AD  - Department of General Surgery, Singapore General Hospital, Singapore.
FAU - Chung, Alexander
AU  - Chung A
AD  - Department of General Surgery, Singapore General Hospital, Singapore.
FAU - Soo, Khee Chee
AU  - Soo KC
AD  - Laboratory of Molecular Endocrinology, Division of Molecular and Cellular 
      Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 
      Singapore.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090209
PL  - England
TA  - J Cell Mol Med
JT  - Journal of cellular and molecular medicine
JID - 101083777
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzenesulfonates)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Pyridines)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Benzenesulfonates/*pharmacology
MH  - Cell Division/*drug effects
MH  - Cell Line, Tumor
MH  - Liver Neoplasms, Experimental/*pathology
MH  - Mice
MH  - Niacinamide/analogs & derivatives
MH  - Phenylurea Compounds
MH  - Phosphorylation
MH  - Pyridines/*pharmacology
MH  - Sirolimus/*pharmacology
MH  - Sorafenib
PMC - PMC6529971
EDAT- 2009/02/18 09:00
MHDA- 2010/07/20 06:00
PMCR- 2009/08/01
CRDT- 2009/02/18 09:00
PHST- 2009/02/18 09:00 [entrez]
PHST- 2009/02/18 09:00 [pubmed]
PHST- 2010/07/20 06:00 [medline]
PHST- 2009/08/01 00:00 [pmc-release]
AID - JCMM692 [pii]
AID - 10.1111/j.1582-4934.2009.00692.x [doi]
PST - ppublish
SO  - J Cell Mol Med. 2009 Aug;13(8B):2673-2683. doi: 10.1111/j.1582-4934.2009.00692.x. 
      Epub 2009 Feb 9.