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Continuous administration of the mTORC1 inhibitor everolimus induces tolerance and decreases autophagy in mice
Author(s) -
Kurdi Ammar,
De Doncker Mireille,
Leloup Arthur,
Neels Hugo,
Timmermans JeanPierre,
Lemmens Katrien,
Apers Sandra,
De Meyer Guido R Y,
Martinet Wim
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13626
Subject(s) - everolimus , autophagy , mtorc1 , pharmacology , pi3k/akt/mtor pathway , in vivo , ulk1 , chemistry , medicine , biology , kinase , signal transduction , protein kinase a , biochemistry , apoptosis , microbiology and biotechnology , ampk
Background and Purpose Everolimus is an allosteric inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1) widely known for its potent autophagy stimulating properties. Because everolimus shows poor solubility and stability in aqueous solutions, long‐term in vivo administration in preclinical models is challenging. The aim of the present study was to evaluate the effects of short‐term and long‐term everolimus administration on mTORC1 inhibition and autophagy induction in mice. Experimental Approach We developed a vehicle in which everolimus was solubilized and stable at 37°C for at least 1 month. Using osmotic minipumps, GFP microtubule‐associated protein light chain 3 transgenic mice were treated continuously either with vehicle or everolimus (1.5 mg·kg −1 per day) for 3 or 28 days. Alternatively, a regimen consisting of intermittent everolimus administration (every other day) for 56 days by oral gavage was used. Autophagy markers and mTORC1 activation status were investigated in the liver. Key Results As expected, everolimus inhibited mTORC1 and stimulated autophagy in the liver after 3 days of treatment. However, continuous administration for 28 days resulted in hyperactivation of the Akt1‐mTORC1 pathway accompanied by a remarkable decrease in autophagy markers. Everolimus given intermittently for 56 days partially rescued mTORC1 sensitivity to the drug but without inducing autophagy. The failure to induce autophagy following long‐term everolimus administration was due to uncoupling of the mTORC1 substrate unc‐51 like autophagy activating kinase 1. Conclusions and Implications Our data encourage the use of intermittent everolimus regimens to prevent tolerance and to extend its activity.