PMID- 22401294
OWN - NLM
STAT- MEDLINE
DCOM- 20120625
LR  - 20220409
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 12
DP  - 2012 Mar 8
TI  - Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells.
PG  - 86
LID - 10.1186/1471-2407-12-86 [doi]
AB  - BACKGROUND: The mammalian target of rapamycin (mTOR) is frequently activated in 
      colon cancers due to mutations in the phosphatidylinositol 3-kinase (PI3K) 
      pathway. Targeting mTOR with allosteric inhibitors of mTOR such as rapamycin 
      reduces colon cancer progression in several experimental models. Recently, a new 
      class of mTOR inhibitors that act as ATP-competitive inhibitors of mTOR, has been 
      developed. The effectiveness of these drugs in colon cancer cells has however not 
      been fully characterized. METHODS: LS174T, SW480 and DLD-1 colon cancer cell 
      lines were treated with PP242 an ATP-competitive inhibitor of mTOR, NVP-BEZ235, a 
      dual PI3K/mTOR inhibitor or rapamycin. Tumor cell growth, proliferation and 
      survival were assessed by MTS assay, 5-bromo-2'-deoxyuridine (BrDU) incorporation 
      or by quantification of DNA fragmentation respectively. In vivo, the anticancer 
      activity of mTOR inhibitors was evaluated on nude mice bearing colon cancer 
      xenografts. RESULTS: PP242 and NVP-BEZ235 reduced the growth, proliferation and 
      survival of LS174T and DLD-1 colon cancer cells more efficiently than rapamycin. 
      Similarly, PP242 and NVP-BEZ235 also decreased significantly the proliferation 
      and survival of SW480 cells which were resistant to the effects of rapamycin. In 
      vivo, PP242 and NVP-BEZ235 reduced the growth of xenografts generated from LS174T 
      and SW480 cells. Finally, we also observed that the efficacy of ATP-competitive 
      inhibitors of mTOR was enhanced by U0126, a MEK inhibitor. CONCLUSIONS: Taken 
      together, these results show that ATP-competitive inhibitors of mTOR are 
      effective in blocking colon cancer cell growth in vitro and in vivo and thus 
      represent a therapeutic option in colon cancer either alone or in combination 
      with MEK inhibitors.
FAU - Blaser, Benjamin
AU  - Blaser B
AD  - Department of Visceral Surgery, Centre Hospitalier Universitaire Vaudois and 
      University of Lausanne, Pavillon 4, Av, de Beaumont, 1011 Lausanne, Switzerland.
FAU - Waselle, Laurent
AU  - Waselle L
FAU - Dormond-Meuwly, Anne
AU  - Dormond-Meuwly A
FAU - Dufour, Marc
AU  - Dufour M
FAU - Roulin, Didier
AU  - Roulin D
FAU - Demartines, Nicolas
AU  - Demartines N
FAU - Dormond, Olivier
AU  - Dormond O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120308
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Imidazoles)
RN  - 0 (Indoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Purines)
RN  - 0 (Quinolines)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - H5669VNZ7V (PP242)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Colonic Neoplasms/*drug therapy/pathology
MH  - Female
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Immunohistochemistry
MH  - Indoles/pharmacology
MH  - Male
MH  - Mice
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Purines/pharmacology
MH  - Quinolines/pharmacology
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Xenograft Model Antitumor Assays
PMC - PMC3314574
EDAT- 2012/03/10 06:00
MHDA- 2012/06/26 06:00
PMCR- 2012/03/08
CRDT- 2012/03/10 06:00
PHST- 2011/10/20 00:00 [received]
PHST- 2012/03/08 00:00 [accepted]
PHST- 2012/03/10 06:00 [entrez]
PHST- 2012/03/10 06:00 [pubmed]
PHST- 2012/06/26 06:00 [medline]
PHST- 2012/03/08 00:00 [pmc-release]
AID - 1471-2407-12-86 [pii]
AID - 10.1186/1471-2407-12-86 [doi]
PST - epublish
SO  - BMC Cancer. 2012 Mar 8;12:86. doi: 10.1186/1471-2407-12-86.