Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells.

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Version: author
Serval ID
serval:BIB_6C2D06996898
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells.
Journal
BMC Cancer
Author(s)
Blaser B., Waselle L., Dormond-Meuwly A., Dufour M., Roulin D., Demartines N., Dormond O.
ISSN
1471-2407 (Electronic)
ISSN-L
1471-2407
Publication state
Published
Issued date
2012
Volume
12
Pages
86
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
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.
Keywords
Animals, Antibiotics, Antineoplastic/pharmacology, Blotting, Western, Cell Line, Tumor, Cell Proliferation/drug effects, Cell Survival/drug effects, Colonic Neoplasms/drug therapy, Colonic Neoplasms/pathology, Female, Humans, Imidazoles/pharmacology, Immunohistochemistry, Indoles/pharmacology, Male, Mice, Protein Kinase Inhibitors/pharmacology, Purines/pharmacology, Quinolines/pharmacology, Sirolimus/pharmacology, TOR Serine-Threonine Kinases/antagonists & inhibitors, Xenograft Model Antitumor Assays
Pubmed
Web of science
Open Access
Yes
Create date
26/04/2012 15:13
Last modification date
13/05/2020 14:19
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