PMID- 18602920
OWN - NLM
STAT- MEDLINE
DCOM- 20081002
LR  - 20220316
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Linking)
VI  - 135
IP  - 3
DP  - 2008 Sep
TI  - C-kit inhibition by imatinib mesylate attenuates progenitor cell expansion and 
      inhibits liver tumor formation in mice.
PG  - 969-79, 979.e1
LID - 10.1053/j.gastro.2008.05.077 [doi]
AB  - BACKGROUND & AIMS: Numerous studies have linked the proliferation of liver 
      progenitor cells (LPCs) during chronic liver disease to the risk for development 
      of hepatocellular carcinoma. Thus, selective inhibition of LPC growth during 
      preneoplastic injury may prevent or delay the onset of liver cancer. Rats 
      carrying a germ-line mutation in c-kit have an impaired LPC response to liver 
      injury. Therefore, we hypothesized that the c-kit inhibitor imatinib mesylate 
      (IM) would suppress LPC growth and, therefore, may exert antitumorigenic effects 
      in the liver. METHODS: Expression of IM target proteins was examined in 
      chronically injured rodent and human livers. The effect of IM was examined in 
      vitro using LPC lines and in vivo in mice fed a choline-deficient, 
      ethionine-supplemented (CDE) diet. Livers were examined following short-term (up 
      to 1 month) or long-term (up to 14 months) feeding of CDE diet and drug 
      treatments. RESULTS: C-kit was significantly up-regulated in chronic injury and 
      expressed by LPCs. IM was antiproliferative to LPC lines, and knockdown of c-kit 
      reduced this response. IM treatment inhibited the LPCs response and early 
      fibrogenesis induced by a short-term CDE diet. On the longer term, IM treatment 
      reduced the extent of fibrosis and significantly inhibited tumor formation. 
      CONCLUSIONS: Tyrosine kinase inhibitors, such as IM, may be suited for the 
      prevention of hepatocellular carcinoma in the setting of chronic liver injury via 
      antiproliferative effects on c-kit-expressing LPCs.
FAU - Knight, Belinda
AU  - Knight B
AD  - School of Medicine and Pharmacology, Centre for Medical Research, University of 
      Western Australia, Fremantle, Western Australia, Australia. 
      Belinda.Knight@uwa.edu.au
FAU - Tirnitz-Parker, Janina E E
AU  - Tirnitz-Parker JE
FAU - Olynyk, John K
AU  - Olynyk JK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080603
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (Piperazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
RN  - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor alpha)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins c-abl)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - N91BDP6H0X (Choline)
RN  - WX1BN24WZT (Ethionine)
SB  - IM
CIN - Gastroenterology. 2008 Sep;135(3):733-5. PMID: 18692053
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Benzamides
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Cell Survival/drug effects
MH  - Choline/administration & dosage
MH  - Diet
MH  - Dose-Response Relationship, Drug
MH  - Ethionine/administration & dosage
MH  - Hepatitis B, Chronic/metabolism/pathology
MH  - Hepatocytes/*drug effects/pathology
MH  - Humans
MH  - Imatinib Mesylate
MH  - In Vitro Techniques
MH  - Liver/drug effects/metabolism
MH  - Liver Neoplasms, Experimental/metabolism/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Piperazines/*pharmacology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-abl/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Proto-Oncogene Proteins c-kit/*metabolism
MH  - Pyrimidines/*pharmacology
MH  - Receptor, Platelet-Derived Growth Factor alpha/metabolism
MH  - Stem Cells/*drug effects/pathology
EDAT- 2008/07/08 09:00
MHDA- 2008/10/03 09:00
CRDT- 2008/07/08 09:00
PHST- 2007/10/22 00:00 [received]
PHST- 2008/05/08 00:00 [revised]
PHST- 2008/05/29 00:00 [accepted]
PHST- 2008/07/08 09:00 [pubmed]
PHST- 2008/10/03 09:00 [medline]
PHST- 2008/07/08 09:00 [entrez]
AID - S0016-5085(08)00952-9 [pii]
AID - 10.1053/j.gastro.2008.05.077 [doi]
PST - ppublish
SO  - Gastroenterology. 2008 Sep;135(3):969-79, 979.e1. doi: 
      10.1053/j.gastro.2008.05.077. Epub 2008 Jun 3.