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Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects

Renal Unit, Department of Medicine, University/Hospital of Verona, 37126 Verona, Italy
Liver Transplant Unit, Department of General Surgery and Odontoiatrics, University/Hospital of Verona, 37126 Verona, Italy
Department of Pathology and Diagnostics, University of Verona, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy
Nephrology, Dialysis and Transplantation Unit, University of Foggia, 71122 Foggia, Italy
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: William Chi-shing Cho
Int. J. Mol. Sci. 2016, 17(5), 735;
Received: 10 March 2016 / Revised: 21 April 2016 / Accepted: 6 May 2016 / Published: 14 May 2016
(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)
PDF [1086 KB, uploaded 14 May 2016]


Sirolimus (SRL) and everolimus (EVR) are mammalian targets of rapamycin inhibitors (mTOR-I) largely employed in renal transplantation and oncology as immunosuppressive/antiproliferative agents. SRL was the first mTOR-I produced by the bacterium Streptomyces hygroscopicus and approved for several medical purposes. EVR, derived from SRL, contains a 2-hydroxy-ethyl chain in the 40th position that makes the drug more hydrophilic than SRL and increases oral bioavailability. Their main mechanism of action is the inhibition of the mTOR complex 1 and the regulation of factors involved in a several crucial cellular functions including: protein synthesis, regulation of angiogenesis, lipid biosynthesis, mitochondrial biogenesis and function, cell cycle, and autophagy. Most of the proteins/enzymes belonging to the aforementioned biological processes are encoded by numerous and tightly regulated genes. However, at the moment, the polygenic influence on SRL/EVR cellular effects is still not completely defined, and its comprehension represents a key challenge for researchers. Therefore, to obtain a complete picture of the cellular network connected to SRL/EVR, we decided to review major evidences available in the literature regarding the genetic influence on mTOR-I biology/pharmacology and to build, for the first time, a useful and specific “SRL/EVR genes-focused pathway”, possibly employable as a starting point for future in-depth research projects. View Full-Text
Keywords: mTOR inhibitors; sirolimus; everolimus; transplantation; genes mTOR inhibitors; sirolimus; everolimus; transplantation; genes

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Granata, S.; Dalla Gassa, A.; Carraro, A.; Brunelli, M.; Stallone, G.; Lupo, A.; Zaza, G. Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects. Int. J. Mol. Sci. 2016, 17, 735.

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