PMID- 20860815
OWN - NLM
STAT- MEDLINE
DCOM- 20110120
LR  - 20220330
IS  - 1476-4598 (Electronic)
IS  - 1476-4598 (Linking)
VI  - 9
DP  - 2010 Sep 22
TI  - Salirasib inhibits the growth of hepatocarcinoma cell lines in vitro and tumor 
      growth in vivo through ras and mTOR inhibition.
PG  - 256
LID - 10.1186/1476-4598-9-256 [doi]
AB  - BACKGROUND: Dysregulation of epidermal growth factor and insulin-like growth 
      factor signaling play important roles in human hepatocellular carcinoma (HCC), 
      leading to frequent activation of their downstream targets, the 
      ras/raf/extracellular signal-regulated kinase (ERK) and the phosphoinositide 
      3-kinase (PI3K)/Akt/mammalian Target of Rapamycin (mTOR) pathways. Salirasib is 
      an S-prenyl-cysteine analog that has been shown to block ras and/or mTOR 
      activation in several non hepatic tumor cell lines. We investigated in vitro the 
      effect of salirasib on cell growth as well as its mechanism of action in human 
      hepatoma cell lines (HepG2, Huh7, and Hep3B) and its in vivo effect in a 
      subcutaneous xenograft model with HepG2 cells. RESULTS: Salirasib induced a time 
      and dose dependent growth inhibition in hepatocarcinoma cells through inhibition 
      of proliferation and partially through induction of apoptosis. A 50 percent 
      reduction in cell growth was obtained in all three cell lines at a dose of 150 muM 
      when they were cultured with serum. By contrast, salirasib was more potent at 
      reducing cell growth after stimulation with EGF or IGF2 under serum-free 
      conditions, with an IC50 ranging from 60 muM to 85 muM. The drug-induced 
      anti-proliferative effect was associated with downregulation of cyclin A and to a 
      lesser extent of cyclin D1, and upregulation of p21 and p27. Apoptosis induction 
      was related to a global pro-apoptotic balance with caspase 3 activation, 
      cytochrome c release, death receptor upregulation, and a reduced mRNA expression 
      of the apoptosis inhibitors cFLIP and survivin. These effects were associated 
      with ras downregulation and mTOR inhibition, without reduction of ERK and Akt 
      activation. In vivo, salirasib reduced tumour growth from day 5 onwards. After 12 
      days of treatment, mean tumor weight was diminished by 56 percent in the treated 
      animals. CONCLUSIONS: Our results show for the first time that salirasib inhibits 
      the growth of human hepatoma cell lines through inhibition of proliferation and 
      induction of apoptosis, which is associated with ras and mTOR inhibition. The 
      therapeutic potential of salirasib in human HCC was further confirmed in a 
      subcutaneous xenograft model.
FAU - Charette, Nicolas
AU  - Charette N
AD  - Laboratory of Gastroenterology, Institut de Recherche Experimentale et Clinique, 
      Universite Catholique de Louvain, 1200 Brussels, Belgium.
FAU - De Saeger, Christine
AU  - De Saeger C
FAU - Lannoy, Valerie
AU  - Lannoy V
FAU - Horsmans, Yves
AU  - Horsmans Y
FAU - Leclercq, Isabelle
AU  - Leclercq I
FAU - Starkel, Peter
AU  - Starkel P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100922
PL  - England
TA  - Mol Cancer
JT  - Molecular cancer
JID - 101147698
RN  - 0 (Antineoplastic Agents)
RN  - 0 (BIRC5 protein, human)
RN  - 0 (Cyclin A)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Salicylates)
RN  - 0 (Survivin)
RN  - 0 (farnesylthiosalicylic acid)
RN  - 136601-57-5 (Cyclin D1)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
RN  - 4602-84-0 (Farnesol)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - 67763-97-7 (Insulin-Like Growth Factor II)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Animals
MH  - *Antineoplastic Agents/pharmacology/therapeutic use
MH  - Apoptosis/drug effects/genetics
MH  - Blotting, Western
MH  - Carcinoma, Hepatocellular/drug therapy/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cyclin A/genetics
MH  - Cyclin D1/genetics
MH  - Cyclin-Dependent Kinase Inhibitor p21/genetics
MH  - Cyclin-Dependent Kinase Inhibitor p27/genetics
MH  - Epidermal Growth Factor/pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/genetics
MH  - Farnesol/*analogs & derivatives/pharmacology/therapeutic use
MH  - Female
MH  - Hep G2 Cells
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins
MH  - Insulin-Like Growth Factor II/pharmacology
MH  - Liver Neoplasms/drug therapy/genetics/*metabolism
MH  - Mice
MH  - Mice, Nude
MH  - Microtubule-Associated Proteins/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - *Salicylates/pharmacology/therapeutic use
MH  - Survivin
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Xenograft Model Antitumor Assays
MH  - ras Proteins/genetics/*metabolism
PMC - PMC2955616
EDAT- 2010/09/24 06:00
MHDA- 2011/01/21 06:00
PMCR- 2010/09/22
CRDT- 2010/09/24 06:00
PHST- 2010/04/27 00:00 [received]
PHST- 2010/09/22 00:00 [accepted]
PHST- 2010/09/24 06:00 [entrez]
PHST- 2010/09/24 06:00 [pubmed]
PHST- 2011/01/21 06:00 [medline]
PHST- 2010/09/22 00:00 [pmc-release]
AID - 1476-4598-9-256 [pii]
AID - 10.1186/1476-4598-9-256 [doi]
PST - epublish
SO  - Mol Cancer. 2010 Sep 22;9:256. doi: 10.1186/1476-4598-9-256.