PMID- 19845851
OWN - NLM
STAT- MEDLINE
DCOM- 20100225
LR  - 20211203
IS  - 1478-3231 (Electronic)
IS  - 1478-3223 (Linking)
VI  - 30
IP  - 1
DP  - 2010 Jan
TI  - Rapamycin and CCI-779 inhibit the mammalian target of rapamycin signalling in 
      hepatocellular carcinoma.
PG  - 65-75
LID - 10.1111/j.1478-3231.2009.02117.x [doi]
AB  - BACKGROUND: The mammalian target of rapamycin (mTOR), which phosphorylates p70S6K 
      and 4EBP1 and activates the protein translation process, is upregulated in 
      cancers and its activation may be involved in cancer development. AIMS: In this 
      study, we investigated the tumour-suppressive effects of rapamycin and its new 
      analogue CCI-779 on hepatocellular carcinoma (HCC). METHODS: Rapamycin and its 
      new analogue CCI-779 were applied to treat HCC cells. Cell proliferation, cell 
      cycle profile and tumorigenicity were analysed. RESULTS: In human HCCs, we 
      observed frequent (67%, 37/55) overexpression of mTOR transcripts using real-time 
      reverse transcriptase-polymerase chain reaction. Upon drug treatment, PLC/PRF/5 
      showed the greatest reduction in cell proliferation using the colony formation 
      assay, as compared with HepG2, Hep3B and HLE. Rapamycin was a more potent 
      antiproliferative agent than CCI-779 in HCC cell lines. Proliferation assays by 
      cell counting showed that the IC(50) value of rapamycin was lower than that of 
      CCI-779 in PLC/PRF/5 cells. Furthermore, flow cytometric analysis showed that 
      both drugs could arrest HCC cells in the G(1) phase but did not induce apoptosis 
      of these cells, suggesting that these mTOR inhibitors are cytostatic rather than 
      cytotoxic. Upon rapamycin and CCI-779 treatment, the phosphorylation level of 
      mTOR and p70S6K in HCC cell lines was significantly reduced, indicating that both 
      drugs can suppress mTOR activity in HCC cells. In addition, both drugs 
      significantly inhibited the growth of xenografts of PLC/PRF/5 cells in nude mice. 
      CONCLUSIONS: Our findings indicate that rapamycin and its clinical analogue 
      CCI-779 possess tumour-suppressive functions towards HCC cells.
FAU - Hui, Ivan Chun-Fai
AU  - Hui IC
AD  - Liver Cancer and Hepatitis Research Laboratory, Department of Pathology, LKS 
      Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
FAU - Tung, Edmund Kwok-Kwan
AU  - Tung EK
FAU - Sze, Karen Man-Fong
AU  - Sze KM
FAU - Ching, Yick-Pang
AU  - Ching YP
FAU - Ng, Irene Oi-Lin
AU  - Ng IO
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091020
PL  - United States
TA  - Liver Int
JT  - Liver international : official journal of the International Association for the 
      Study of the Liver
JID - 101160857
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 624KN6GM2T (temsirolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Carcinoma, Hepatocellular/*drug therapy/metabolism/pathology
MH  - Cell Count
MH  - Cell Line, Transformed
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Drug Screening Assays, Antitumor
MH  - Female
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/antagonists & inhibitors/*drug 
      effects/metabolism
MH  - Liver Neoplasms/*drug therapy/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/*drug 
      effects/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*analogs & derivatives/*pharmacology
MH  - TOR Serine-Threonine Kinases
EDAT- 2009/10/23 06:00
MHDA- 2010/02/26 06:00
CRDT- 2009/10/23 06:00
PHST- 2009/10/23 06:00 [entrez]
PHST- 2009/10/23 06:00 [pubmed]
PHST- 2010/02/26 06:00 [medline]
AID - LIV2117 [pii]
AID - 10.1111/j.1478-3231.2009.02117.x [doi]
PST - ppublish
SO  - Liver Int. 2010 Jan;30(1):65-75. doi: 10.1111/j.1478-3231.2009.02117.x. Epub 2009 
      Oct 20.