PMID- 21224070
OWN - NLM
STAT- MEDLINE
DCOM- 20110418
LR  - 20211203
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 178
IP  - 1
DP  - 2011 Jan
TI  - Targeting the PI3K/mTOR pathway in murine endocrine cell lines: in vitro and in 
      vivo effects on tumor cell growth.
PG  - 336-44
LID - 10.1016/j.ajpath.2010.11.023 [doi]
AB  - The mammalian target of rapamycin (mTOR) inhibitors, such as rapalogues, are a 
      promising new tool for the treatment of metastatic gastroenteropancreatic 
      endocrine tumors. However, their mechanisms of action remain to be established. 
      We used two murine intestinal endocrine tumoral cell lines, STC-1 and GLUTag, to 
      evaluate the antitumor effects of rapamycin in vitro and in vivo in a preclinical 
      model of liver endocrine metastases. In vitro, rapamycin inhibited the 
      proliferation of cells in the basal state and after stimulation by insulin-like 
      growth factor-1. Simultaneously, p70S6 kinase and 4EBP1 phosphorylation was 
      inhibited. In vivo, rapamycin substantially inhibited the intrahepatic growth of 
      STC-1 cells, irrespectively of the timing of its administration and even when the 
      treatment was administered after cell intrahepatic engraftment. In addition, 
      treated animals had significantly prolonged survival (mean survival time: 47.7 
      days in treated animals versus 31.8 days in controls) and better clinical status. 
      Rapamycin treatment was associated with a significant decrease in mitotic index 
      and in intratumoral vascular density within STC-1 tumors. Furthermore, the 
      antitumoral effect obtained after treatment with a combination of rapamycin and 
      phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was more significant than 
      with rapamycin alone in both cell lines. Our results suggest that the antitumor 
      efficacy of rapamycin in neuroendocrine tumors results from a combination of 
      antiproliferative and antiangiogenic effects. Interestingly, a more potent 
      antitumor efficiency could be obtained by simultaneously targeting several levels 
      of the PI3K/mTOR pathway.
CI  - Copyright A(c) 2011 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Couderc, Christophe
AU  - Couderc C
AD  - INSERM, U865, Faculte Laennec, Universite Claude Bernard Lyon 1, Lyon, France.
FAU - Poncet, Gilles
AU  - Poncet G
FAU - Villaume, Karine
AU  - Villaume K
FAU - Blanc, Martine
AU  - Blanc M
FAU - Gadot, Nicolas
AU  - Gadot N
FAU - Walter, Thomas
AU  - Walter T
FAU - Lepinasse, Florian
AU  - Lepinasse F
FAU - Hervieu, Valerie
AU  - Hervieu V
FAU - Cordier-Bussat, Martine
AU  - Cordier-Bussat M
FAU - Scoazec, Jean-Yves
AU  - Scoazec JY
FAU - Roche, Colette
AU  - Roche C
LA  - eng
PT  - Journal Article
DEP - 20101223
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/*therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols
MH  - Carcinoma, Neuroendocrine/*drug therapy/enzymology/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Chromones/*therapeutic use
MH  - Intestinal Neoplasms/*drug therapy/enzymology/pathology
MH  - Mice
MH  - Morpholines/*therapeutic use
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Protein Kinase Inhibitors/*therapeutic use
MH  - Sirolimus/*therapeutic use
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
PMC - PMC3069842
EDAT- 2011/01/13 06:00
MHDA- 2011/04/19 06:00
PMCR- 2012/01/01
CRDT- 2011/01/13 06:00
PHST- 2010/03/04 00:00 [received]
PHST- 2010/08/13 00:00 [revised]
PHST- 2010/09/09 00:00 [accepted]
PHST- 2011/01/13 06:00 [entrez]
PHST- 2011/01/13 06:00 [pubmed]
PHST- 2011/04/19 06:00 [medline]
PHST- 2012/01/01 00:00 [pmc-release]
AID - S0002-9440(10)00069-6 [pii]
AID - AJPA68 [pii]
AID - 10.1016/j.ajpath.2010.11.023 [doi]
PST - ppublish
SO  - Am J Pathol. 2011 Jan;178(1):336-44. doi: 10.1016/j.ajpath.2010.11.023. Epub 2010 
      Dec 23.