Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases

Lebwohl, David; Anak, Özlem; Sahmoud, Tarek; Klimovsky, Judith; Elmroth, Ingrid; Haas, T; Posluszny, Joseph A.; Saletan, Stephen; Berg, William J.

doi:10.1111/nyas.12122

Cited by 75 publications

(49 citation statements)

References 65 publications

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“…As an inhibitor of mTOR, everolimus has been intensively studied for its ability to inhibit mTOR complex 1 (mTORC1) and sequential inhibition of S6K activation (phosphorylation) and 4EBP1 inhibition (phosphorylation) to suppress cell proliferation [6,11,15]. S6K1 directly phosphorylates the 40S ribosomal protein S6, which increases the translation of mRNA, and 4EBP1 is a repressor of translation initiation [21].…”

Section: Discussionmentioning

confidence: 99%

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Enhanced Autophagy by Everolimus Contributes to the Antirestenotic Mechanisms in Vascular Smooth Muscle Cells

Tang

Dong²,

Wei³

et al. 2014

J Vasc Res

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Objective: The present study aims to investigate the underlying mechanisms accounting for the activities of everolimus to inhibit the growth of vascular smooth muscle cells (VSMCs), which contributes to restenosis. Methods: Primary VSMCs were cultured in media containing smooth muscle growth supplements and incubated with testing agents. Cell proliferation, cell cycle distribution, apoptosis and autophagy, and the key molecules involved, were examined. Results: Everolimus inhibited the proliferation of VSMCs by inhibiting the activation of ribosomal protein S6 kinase and phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1, and downregulating proliferating cellular nuclear antigen. Everolimus induced cell cycle arrest at the G₁ phase by downregulating cyclin D1 and upregulating p27, and increased apoptosis by downregulating Bcl-2, upregulating Bad and activating capsase-3 and poly ADP ribose polymerase. Everolimus enhanced autophagy by increasing the conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II, and upregulating Beclin 1. Specific autophagy inhibitors, 3-methyladenine and bafilomycin A1, significantly attenuated the inhibition of cell proliferation, the increased apoptosis and the altered expression of the above key proteins induced by everolimus. Conclusions: Enhanced autophagy by everolimus contributes to its antirestenotic activity and its abilities to inhibit cell proliferation and to induce apoptosis of VSMCs.

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Section: Discussionmentioning

confidence: 99%

“…Sporadic studies have investigated its role as an antiproliferative agent in rat [10] and human [4] VSMCs. The rationale for using everolimus to prevent restenosis is largely based on its actions on cancer cells [11] and on the effects of its pharmacological ‘relatives', including sirolimus and rapamycin, on VSMCs [12,13,14]. …”

Section: Introductionmentioning

confidence: 99%

Enhanced Autophagy by Everolimus Contributes to the Antirestenotic Mechanisms in Vascular Smooth Muscle Cells

Tang

Dong²,

Wei³

et al. 2014

J Vasc Res

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“…Similar to rapamycin, everolimus and cyclophilin FKBP-12 complex binds to the serine/threonine kinase mTOR and inhibits downstream signalling pathways for cell growth and proliferation (10)(11)(12). Although initially developed for the acute and chronic rejection of cardiac, liver, lung, and renal transplant recipients, everolimus is currently being used for the treatment of many cancer types, including renal cell carcinoma, pancreatic neuroendocrine tumors, and breast cancer (13,14). As a novel proliferation inhibitor, the use of everolimus in various diseases is still ongoing.…”

Section: Introductionmentioning

confidence: 99%

Effects of everolimus on a rat model of cerulein-induced experimental acute pancreatitis

Özkardeş¹,

Bozkurt²,

Dumlu³

et al. 2015

UCD

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Objective: To analyze the biochemical and histopathological effects of everolimus in an experimental rat model of cerulein-induced acute pancreatitis. The aim of the present study was to determine the effects of everolimus on blood biochemical parameters and tissue histopathology in an experimental rat model of cerulein-induced acute pancreatitis. Material and Methods:In 30 Wistar albino rats (male; 240-260 g), acute pancreatitis was induced by an intraperitoneal injection of cerulein (50 μg/kg) administered twice in 2 h. They were equally divided into the following three groups: 0.9% isotonic solution (Group 1; control), everolimus once (Group 2), and everolimus twice (Group 3) by oral gavage after cerulein injection. Thirty hours after the induction of pancreatitis, blood samples were collected by direct intracardiac puncture, rats were sacrificed, and pancreatic tissue samples were obtained.Results: Biochemical analyses of the blood samples showed statistically significant difference in red blood cell count as well as hemoglobin, hematocrit, urea, and alanine transaminase levels among the study groups (p<0.05 in all). Everolimus proved to significantly increase red blood cell count in a dose-independent manner. Hemoglobin and hematocrit levels significantly increased only after treatment with one dose of everolimus. Urea level was significantly different between the Groups 2 and 3; however, no change was observed in both groups when compared with the control. Alanine transaminase level significantly decreased only after treatment with two doses of everolimus. Histopathological analyses revealed that everolimus significantly decreased inflammation and perivascular infiltrate in a dose-dependent manner (35% in Group 2, 75% in Group 3; p=0.048). Conclusion:Treatment with two doses of everolimus improved some biochemical and histopathological parameters of experimental rat models of cerulein-induced acute pancreatitis and implied the specific inhibition of inflammatory response pathways. Keywords: Pancreatitis, cerulein, everolimus, inflammation INTRODUCTIONAcute pancreatitis is a localized inflammatory condition with a high mortality rate (2.1%-9.2%) worldwide. Because of its potential to trigger systemic inflammatory response, it can cause multiple organ failure (1, 2). The common causes of acute pancreatitis are alcohol abuse or gallstone disease (60%-75% of the cases) followed by hypertriglyceridemia, hyperparathyroidism, pancreatic malignancy, endoscopic retrograde cholangiopancreatography, trauma, infectious agents (increasingly associated with HIV infection), drugs (such as tetracycline, azathioprine, ethinyl estradiol, mercaptopurine, and sulfamethoxazole), autoimmunity, abdominal trauma, ischemia, diabetes mellitus, porphyria, and heredity (3-5).Although the disease is common, the treatment of acute pancreatitis is still very limited. There are only a number of pharmacological approaches, which are mostly supportive involving adequate fluid resuscitation and oxygen supplementation, to maintain normal art...

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“…The gene product of TSC1 and TSC2, hamartin and tuberin, respectively, form a heterodimeric complex that regulate the mTOR pathway by its effects on Rheb (Ras homolog enriched in brain) to inhibit mTOR signaling (Figure). 39,43 Mutations in TSC1 or TSC2 will disrupt the complex and lead to direct activation of mTOR signaling, and in essence cause increased cell proliferation and growth. …”

Section: Mammalian Target Of Rapamycin In Tuberous Sclerosis Complexmentioning

confidence: 99%

Long-Term Everolimus Treatment in Individuals With Tuberous Sclerosis Complex: A Review of the Current Literature

Tran

Zupanc

2015

Pediatric Neurology

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Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases

Cited by 75 publications

References 65 publications

Enhanced Autophagy by Everolimus Contributes to the Antirestenotic Mechanisms in Vascular Smooth Muscle Cells

Enhanced Autophagy by Everolimus Contributes to the Antirestenotic Mechanisms in Vascular Smooth Muscle Cells

Effects of everolimus on a rat model of cerulein-induced experimental acute pancreatitis

Long-Term Everolimus Treatment in Individuals With Tuberous Sclerosis Complex: A Review of the Current Literature

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