Advances in the therapeutic use of mammalian target of rapamycin (mTOR) inhibitors in dermatology

Mammalian target of rapamycin (mTOR) is a PI3K-related serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism, in response to nutrient and hormonal stimuli. mTOR functions in two distinct complexes—mTORC1 is sensitive to rapamycin, while, mTORC2 is insensitive to this drug. Deregulation of mTOR’s enzymatic activity has roles in cancer, obesity, and aging. Rapamycin and its chemical derivatives are the only drugs that inhibit the hyperactivity of mTOR, but numerous side effects have been described due to its therapeutic use. The purpose of this study was to identify new compounds of natural origin that can lead to drugs with fewer side effects. We have used computational techniques (molecular docking and calculated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters) that have enabled the selection of candidate compounds, derived from marine natural products, SuperNatural II, and ZINC natural products, for inhibitors targeting, both, the ATP and the rapamycin binding sites of mTOR. We have shown experimental evidence of the inhibitory activity of eleven selected compounds against mTOR. We have also discovered the inhibitory activity of a new marine extract against this enzyme. The results have been discussed concerning the necessity to identify new molecules for therapeutic use, especially against aging, and with fewer side effects.

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Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells

Endocrine Related Cancer ◽

10.1530/erc-10-0153 ◽

2011 ◽

Vol 18 (5) ◽

pp. 541-554 ◽

Cited By ~ 23

Author(s):

Alessia Di Florio ◽

Laura Adesso ◽

Simona Pedrotti ◽

Gabriele Capurso ◽

Emanuela Pilozzi ◽

...

Keyword(s):

Cell Cycle ◽

Cell Adhesion ◽

Microarray Analysis ◽

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Target Of Rapamycin ◽

Cell Cycle Regulators ◽

Inhibition Of Proliferation ◽

Pancreatic Endocrine Tumours ◽

Independent Marker

Pancreatic endocrine tumours (PETs) are rare and heterogeneous neoplasms, often diagnosed at metastatic stage, for which no cure is currently available. Recently, activation of two pathways that support proliferation and invasiveness of cancer cells, the Src family kinase (SFK) and mammalian target of rapamycin (mTOR) pathways, was demonstrated in PETs. Since both pathways represent suitable targets for therapeutic intervention, we investigated their possible interaction in PETs. Western blot and immunofluorescence analyses indicated that SFK and mTOR activity correlate in PET cell lines. We also found that SFKs coordinate cell adhesion and spreading with activation of the mTOR pathway in PET cells. Live cell metabolic labelling and biochemical studies demonstrated that SFK activity enhance mTOR-dependent translation initiation. Furthermore, microarray analysis of the mRNAs associated with polyribosomes revealed that SFKs regulate mTOR-dependent translation of specific transcripts, with an enrichment in mRNAs encoding cell cycle proteins. Importantly, a synergic inhibition of proliferation was observed in PET cells concomitantly treated with SFK and mTOR inhibitors, without activation of the phosphatidylinositol 3-kinase/AKT pro-survival pathway. Tissue microarray analysis revealed activation of Src and mTOR in some PET samples, and identified phosphorylation of 4E-BP1 as an independent marker of poor prognosis in PETs. Thus, our work highlights a novel link between the SFK and mTOR pathways, which regulate the translation of mRNAs for cell cycle regulators, and suggest that crosstalk between these pathways promotes PET cell proliferation.

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Combinations of Cytotoxic Drugs, Ionizing Radiation, and Mammalian Target of Rapamycin (mTOR) Inhibitors

Multimodal Concepts for Integration of Cytotoxic Drugs - Medical Radiology ◽

10.1007/3-540-35662-2_9 ◽

2006 ◽

pp. 127-137

Author(s):

Jann N. Sarkaria

Keyword(s):

Ionizing Radiation ◽

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Cytotoxic Drugs ◽

Target Of Rapamycin

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Incidence and risk of treatment-related mortality in patients with renal cell cancer (RCC) and non-RCC treated with mammalian target of rapamycin (mTOR) inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.347 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 347-347

Author(s):

Toni K. Choueiri ◽

Youjin Je ◽

Guru Sonpavde ◽

Matt D. Galsky ◽

Marina Kaymakcalan ◽

...

Keyword(s):

Adverse Events ◽

Renal Cell ◽

Fixed Effects ◽

Meta Analysis ◽

Cell Cancer ◽

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Target Of Rapamycin ◽

Therapeutic Modality ◽

Increased Risk

347 Background: Inhibition of the mammalian target of rapamycin (mTOR) is an established therapeutic modality for multiple malignancies including renal cell carcinoma (RCC). Agents that target mTOR have been sporadically associated with an increased risk of potentially life-threatening adverse events. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors, including RCC. Methods: MEDLINE/PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to trials of US Food and Drug Administration—approved mTOR inhibitors (everolimus and temsirolimus) that reported on patients with cancer, randomized design, and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% Confidence Intervals (CIs) by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: In all 2,990 patients from 8 randomized controlled trials (RCTs) were included, 2033 from everolimus trials and 957 from temsirolimus trials. The incidence of FAEs related to mTOR inhibitors use was 3.4% (95% CI, 1.9-6.0) with a RR of 2.33 (95% CI, 1.32 to 4.10; P = .003) compared to control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types (RCC vs. non-RCC). No evidence of publication bias was observed. Conclusions: The use of mTOR inhibitors is associated with an increased risk of FAEs in RCC and non-RCC patients, compared with control patients.

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Kinome-wide Selectivity Profiling of ATP-competitive Mammalian Target of Rapamycin (mTOR) Inhibitors and Characterization of Their Binding Kinetics

Journal of Biological Chemistry ◽

10.1074/jbc.m111.304485 ◽

2012 ◽

Vol 287 (13) ◽

pp. 9742-9752 ◽

Cited By ~ 65

Author(s):

Qingsong Liu ◽

Sivapriya Kirubakaran ◽

Wooyoung Hur ◽

Mario Niepel ◽

Kenneth Westover ◽

...

Keyword(s):

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Binding Kinetics ◽

Target Of Rapamycin

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Response of a Neuronal Model of Tuberous Sclerosis to Mammalian Target of Rapamycin (mTOR) Inhibitors: Effects on mTORC1 and Akt Signaling Lead to Improved Survival and Function

Journal of Neuroscience ◽

10.1523/jneurosci.0955-08.2008 ◽

2008 ◽

Vol 28 (21) ◽

pp. 5422-5432 ◽

Cited By ~ 323

Author(s):

L. Meikle ◽

K. Pollizzi ◽

A. Egnor ◽

I. Kramvis ◽

H. Lane ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Neuronal Model ◽

Akt Signaling ◽

Target Of Rapamycin ◽

And Function

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Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro

Endocrine Related Cancer ◽

10.1677/erc-08-0269 ◽

2009 ◽

Vol 16 (3) ◽

pp. 1017-1027 ◽

Cited By ~ 49

Author(s):

Alexander Gorshtein ◽

Hadara Rubinfeld ◽

Efrat Kendler ◽

Marily Theodoropoulou ◽

Vesna Cerovac ◽

...

Keyword(s):

Cell Proliferation ◽

Cyclin D1 ◽

Pituitary Adenomas ◽

Pituitary Tumor ◽

Mammalian Target Of Rapamycin ◽

Pituitary Tumors ◽

Mtor Inhibitors ◽

Target Of Rapamycin ◽

Gh3 Cells ◽

Mtor Inhibition

The effect of mammalian target of rapamycin (mTOR) inhibitors on pituitary tumors is unknown. Akt overexpression was demonstrated in pituitary adenomas, which may render them sensitive to the anti-proliferative effects of these drugs. The objective of the study was to evaluate the anti-proliferative efficacy of the mTOR inhibitor, rapamycin, and its orally bioavailable analog RAD001 on the GH-secreting pituitary tumor GH3 and MtT/S cells and in human GH-secreting pituitary adenomas (GH-omas) in primary cell cultures. Treatment with rapamycin or RAD001 significantly decreased the number of viable cells and cell proliferation in a dose- and time-dependent manner. This was reflected by decreased phosphorylation levels of the downstream mTOR target p70S6K. Rapamycin treatment of GH3 cells induced G0/G1 cell cycle arrest. In other tumor cell types, this was attributed to a decrease in cyclin D1 levels. However, rapamycin did not affect cyclin D1 protein levels in GH3 cells. By contrast, it decreased cyclin D3 and p21/CIP, which stabilizes cyclin D/cyclin-dependent kinase 4 (cdk4) complexes. Rapamycin inhibited FCS-induced retinoblastoma phosphorylation and subsequent E2F-transcriptional activity. In response to decreased E2F activity, the expression of the E2F-regulated genes cyclin E and cdk2 was reduced. Our results showed that mTOR inhibitors potently inhibit pituitary cell proliferation, suggesting that mTOR inhibition may be a promising anti-proliferative therapy for pituitary adenomas. This therapeutic manipulation may have beneficial effects particularly for patients harboring invasive pituitary tumors resistant to current treatments.

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