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Int. J. Mol. Sci. 2016, 17(5), 735; doi:10.3390/ijms17050735

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

1
Renal Unit, Department of Medicine, University/Hospital of Verona, 37126 Verona, Italy
2
Liver Transplant Unit, Department of General Surgery and Odontoiatrics, University/Hospital of Verona, 37126 Verona, Italy
3
Department of Pathology and Diagnostics, University of Verona, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy
4
Nephrology, Dialysis and Transplantation Unit, University of Foggia, 71122 Foggia, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
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)
View Full-Text   |   Download PDF [1086 KB, uploaded 14 May 2016]   |  

Abstract

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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