Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors.

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State: Public
Version: Final published version
Serval ID
serval:BIB_1EC7442E4D3B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors.
Journal
Molecular cancer
Author(s)
Faes S., Duval A.P., Planche A., Uldry E., Santoro T., Pythoud C., Stehle J.C., Horlbeck J., Letovanec I., Riggi N., Demartines N., Dormond O.
ISSN
1476-4598 (Electronic)
ISSN-L
1476-4598
Publication state
Published
Issued date
05/12/2016
Peer-reviewed
Oui
Volume
15
Number
1
Pages
78
Language
english
Notes
Publication types: Comparative Study ; Journal Article
Publication Status: epublish
Abstract
Blocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study.
Cancer cell lines were treated with rapamycin in acidic or physiological conditions and cell proliferation was investigated. The effect of acidity on mTORC1 activity was determined by Western blot. The anticancer efficacy of rapamycin in combination with sodium bicarbonate to increase the intratumoral pH was tested in two different mouse models and compared to rapamycin treatment alone. Histological analysis was performed on tumor samples to evaluate proliferation, apoptosis and necrosis.
Exposing cancer cells to acidic pH in vitro significantly reduced the anti-proliferative effect of rapamycin. At the molecular level, acidity significantly decreased mTORC1 activity, suggesting that cancer cell proliferation is independent of mTORC1 in acidic conditions. In contrast, the activation of mitogen-activated protein kinase (MAPK) or AKT were not affected by acidity, and blocking MAPK or AKT with a chemical inhibitor maintained an anti-proliferative effect at low pH. In tumor mouse models, the use of sodium bicarbonate increased mTORC1 activity in cancer cells and potentiated the anti-cancer efficacy of rapamycin. Combining sodium bicarbonate with rapamycin resulted in increased tumor necrosis, increased cancer cell apoptosis and decreased cancer cell proliferation as compared to single treatment.
Taken together, these results emphasize the inefficacy of mTORC1 inhibitors in acidic conditions. They further highlight the potential of combining sodium bicarbonate with mTORC1 inhibitors to improve their anti-tumoral efficacy.

Keywords
Acids/adverse effects, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation/drug effects, Cell Survival/drug effects, Colorectal Neoplasms/drug therapy, Colorectal Neoplasms/metabolism, Drug Therapy, Combination, Gene Expression Regulation, Neoplastic/drug effects, HT29 Cells, Humans, Mice, Multiprotein Complexes/antagonists & inhibitors, Multiprotein Complexes/metabolism, Sirolimus/administration & dosage, Sirolimus/pharmacology, Sodium Bicarbonate/administration & dosage, Sodium Bicarbonate/pharmacology, TOR Serine-Threonine Kinases/antagonists & inhibitors, TOR Serine-Threonine Kinases/metabolism, Tumor Microenvironment, Xenograft Model Antitumor Assays, Acidity, Rapamycin, Resistance Mechanisms, Sodium Bicarbonate, mTORC1
Pubmed
Web of science
Open Access
Yes
Create date
12/12/2016 18:27
Last modification date
20/08/2019 12:54
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