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Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their
Intracellular Effects
#MMPMID27187382
Granata S
; Dalla Gassa A
; Carraro A
; Brunelli M
; Stallone G
; Lupo A
; Zaza G
Int J Mol Sci
2016[May]; 17
(5
): ? PMID27187382
show ga
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.
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