المصدر: PLoS ONE. 9/28/2023, Vol. 18 Issue 9, p1-3. 3p.

مصطلحات موضوعية: *MTOR inhibitors, *PANCREATIC cancer, *CANCER cells, *RAPAMYCIN, *METFORMIN, *INSULIN receptors, *AUTHOR-editor relationships

مستخلص: Graph: Fig 3 Differential feedback activation of Akt and ERK phosphorylation by rapamycin and KU63794 in insulin-stimulated MiaPaCa-2 and PANC-1 cells. Fig 3 (Panc-1), pS6K SP Thr389 sp , pAKT SP Ser473 sp , pERK SP T202/Y204 sp . Specifically, Lanes 1-4 of the ERK panel in Fig 3 (PANC-1) appear similar to the ERK panel in Fig 6C despite representing different conditions. [Extracted from the article]

المؤلفون: Gottlieb, Jens, Fischer, Bettina, Schupp, Jonas C., Golpon, Heiko

المصدر: PLoS ONE; 5/18/2023, Vol. 17 Issue 5, p1-13, 13p

مصطلحات موضوعية: LUNG transplantation, LUNGS, IMMUNOSUPPRESSION, CASE-control method, GLOMERULAR filtration rate, MTOR inhibitors, RAPAMYCIN

مستخلص: Background: Data on calcineurin-inhibitor (CNI) free immunosuppression after lung transplantation (LTx) are limited. Aim of this study was to investigate CNI-free immunosuppression using mechanistic target of rapamycin (mTOR) inhibitors. Methods: This retrospective analysis was performed at a single center. Adult patients after LTx without CNI during the follow-up period were included. Outcome was compared to those LTx patients with malignancy who continued CNI. Results: Among 2,099 patients in follow-up, fifty-one (2.4%) were converted median 6.2 years after LTx to a CNI-free regimen combining mTOR inhibitors with prednisolone and an antimetabolite, two patients were switched to mTOR inhibitors with prednisolone only. In 25 patients, malignancies without curative treatment options were the reason of the conversion, with a 1-year survival of 36%. The remaining patients had a 1-year survival of 100%. Most common non-malignant indication was neurological complications (n = 9). Fifteen patients were re-converted to a CNI-based regimen. The median duration of CNI-free immunosuppression was 338 days. No acute rejections were detected in 7 patients with follow-up biopsies. In multivariate analysis, CNI-free immunosuppression were not associated with improved survival after malignancy. The majority of patients with neurological diseases improved 12 months after conversion. Glomerular filtration rate increased by median 5 (25 and 75% percentiles -6; +18) ml/min/1.73 m². Conclusions: mTOR inhibitor based CNI-free immunosuppression may be safely performed in selected patients after LTx. This approach was not associated with improved survival in patients with malignancy. Significant functional improvements were observed in patients with neurological diseases. [ABSTRACT FROM AUTHOR]

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المؤلفون: Mrozek, Evelyn M.¹ (AUTHOR) dk@rics.bwh.harvard.edu, Bajaj, Vineeta¹ (AUTHOR), Guo, Yanan¹ (AUTHOR), Malinowska, Izabela A.¹ (AUTHOR), Zhang, Jianming² (AUTHOR), Kwiatkowski, David J.¹ (AUTHOR) dk@rics.bwh.harvard.edu

المصدر: PLoS ONE. 4/23/2021, Vol. 16 Issue 4, p1-28. 28p.

مصطلحات موضوعية: *MTOR inhibitors, *TUBEROUS sclerosis, *CELL growth, *CELL cycle, *CELL lines

مستخلص: Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored. Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay. [ABSTRACT FROM AUTHOR]

المصدر: PLoS ONE. 1/15/2020, Vol. 15 Issue 1, p1-6. 6p.

مصطلحات موضوعية: *TRANSGLUTAMINASES, *MTOR inhibitors, *PROLIFERATING cell nuclear antigen

المؤلفون: Antonioli, Eliane¹, Torres, Natália¹, Ferretti, Mario¹, Piccinato, Carla de Azevedo¹, Sertie, Andrea Laurato¹ andrea.sertie@einstein.br

المصدر: PLoS ONE. 1/31/2019, Vol. 14 Issue 1, p1-14. 14p.

مصطلحات موضوعية: *MESENCHYMAL stem cells, *MTOR inhibitors, *PROGENITOR cells, *RAPAMYCIN, *PHOSPHORYLATION

مستخلص: Background aims: Delaying replicative senescence and extending lifespan of human mesenchymal stromal cells (MSCs) may enhance their potential for tissue engineering and cell based therapies. Accumulating evidence suggests that inhibitors of the mTOR signaling pathway, such as rapamycin, constitute promising pharmacological agents to retard senescence and extend stemness properties of various progenitor cell types. Here, we investigated whether the ability of rapamycin to postpone replicative senescence varies among bone marrow MSC samples (BM-MSCs) derived from different healthy donors, and explored the molecular mechanisms that drive rapamycin-mediated lifespan increment. Methods: BM-MSCs at early passages were serially passaged either in absence or continuous presence of rapamycin and the number of cell population doublings until growth arrest was measured. The inhibition of mTOR signaling was assessed by the phosphorylation status of the downstream target RPS6. The expression levels of several senescence and pluripotency markers at early and late/senescent passages were analyzed by RT-qPCR, flow cytometry and western blot. Results: We found that the lifespan extension in response to the continuous rapamycin treatment was highly variable among samples, but effective in most BM-MSCs. Despite all rapamycin-treated cells secreted significantly reduced levels of IL6, a major SASP cytokine, and expressed significantly higher levels of the pluripotency marker NANOG, the expression patterns of these markers were not correlated with the rapamycin-mediated increase in lifespan. Interestingly, rapamycin-mediated life-span extension was significantly associated only with repression of p16INK4A protein accumulation. Conclusions: Taken together, our results suggest that some, but not all, BM-MSC samples would benefit from using rapamycin to postpone replicative arrest and reinforce a critical role of p16INK4A protein downregulation in this process. [ABSTRACT FROM AUTHOR]

المؤلفون: Hoff, Uwe, Markmann, Denise, Thurn-Valassina, Daniela, Nieminen-Kelhä, Melina, Erlangga, Zulrahman, Schmitz, Jessica, Bräsen, Jan Hinrich, Budde, Klemens, Melk, Anette, Hegner, Björn

المصدر: PLoS ONE; 4/21/2022, Vol. 17 Issue 4, p1-16, 16p

مصطلحات موضوعية: CELLULAR aging, KIDNEY transplantation, RAPAMYCIN, MTOR inhibitors, REPERFUSION, REPERFUSION injury, ALEMTUZUMAB, MONOCYTES

مستخلص: Interstitial fibrosis and tubular atrophy, a major cause of kidney allograft dysfunction, has been linked to premature cellular senescence. The mTOR inhibitor Rapamycin protects from senescence in experimental models, but its antiproliferative properties have raised concern early after transplantation particularly at higher doses. Its effect on senescence has not been studied in kidney transplantation, yet. Rapamycin was applied to a rat kidney transplantation model (3 mg/kg bodyweight loading dose, 1.5 mg/kg bodyweight daily dose) for 7 days. Low Rapamycin trough levels (2.1–6.8 ng/mL) prevented the accumulation of p16^INK4a positive cells in tubules, interstitium, and glomerula. Expression of the cytokines MCP-1, IL-1β, and TNF-α, defining the proinflammatory senescence-associated secretory phenotype, was abrogated. Infiltration with monocytes/macrophages and CD8⁺ T-lymphocytes was reduced and tubular function was preserved by Rapamycin. Inhibition of mTOR was not associated with impaired structural recovery, higher glucose levels, or weight loss. mTOR inhibition with low-dose Rapamycin in the immediate posttransplant period protected from premature cellular senescence without negative effects on structural and functional recovery from preservation/reperfusion damage, glucose homeostasis, and growth in a rat kidney transplantation model. Reduced senescence might maintain the renal regenerative capacity rendering resilience to future injuries resulting in protection from interstitial fibrosis and tubular atrophy. [ABSTRACT FROM AUTHOR]

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المؤلفون: Brakemeier, Susanne¹ susanne.brakemeier@charite.de, Vogt, Lars², Adams, Lisa², Zukunft, Bianca¹, Diederichs, Gerd², Hamm, Bernd², Budde, Klemens¹, Makowski, Marcus R.^2,3

المصدر: PLoS ONE. 12/12/2017, Vol. 12 Issue 12, p1-12. 12p.

مصطلحات موضوعية: *MTOR inhibitors, *ANGIOMYOLIPOMA, *TUBEROUS sclerosis diagnosis, *TUBEROUS sclerosis, *EVEROLIMUS, *THERAPEUTICS

مستخلص: Purpose: Tuberous sclerosis complex (TSC)-associated renal angiomyolipoma (AML) have a high lifetime risk of acute bleeding. MTOR-inhibitors are a promising novel treatment for TSC-AML, however adequate response to therapy can be difficult to assess. Early changes in MRI signal may serve as a novel early indicator for a satisfactory response to mTOR-inhibitor therapy of AML. Materials and methods: Thirty-eight patients with the definite diagnosis of tuberous sclerosis receiving everolimus therapy and n = 19 patients without specific therapy were included. 1.5 Tesla MRI was performed including sequences with a selective fat suppression. Patients were investigated prior to the initiation of therapy (baseline) and after <3 months (n = 21 patients), 3 to 6 months (n = 32) and 18 to 24 months (n = 28). Signal and size changes of renal AMLs were assessed at all different timepoints. Signal-to-noise-ratio (SNR), contrast-to-noise-ratio (CNR) and size of angiomyolipomas were evaluated. Results: Signal changes in 273 AMLs were evaluated. A significant and strong decrease of the CNR of AMLs following the initiation of therapy was measured in the fat-suppressed MR sequence at all time points, compared to the baseline: From 7.41±6.98 to 3.84±6.25 (p ≤ 0.05p = 0.002), 3.36±6.93 (p<0.0001), and 2.50±6.68 (p<0.0001) after less than 3 months, 3–6 months or 18–24 months of everolimus treatment, respectively. Also, a significant, however less pronounced, reduction of angiomyolipoma size in the different groups was measured (from baseline 2022.2±2657.7 mm2 to 1854.4±1670.9 mm2 (p = 0.009), 1875.5±3190.1 mm2 (p<0.001), and 1365.8 ± 1628.8 mm2 (p<0.0001) after less than 3 months, 3–6 months or 18–24 months of everolimus treatment, respectively). No significant changes in CNR (p>0.05) and size (p>0.05) were measured in the control group. Conclusion: mTOR inhibitor therapy in TSC patients results in an early and pronounced fatty transformation of AMLs on MRI. Fatty transformation could represent a novel early indicator of response to therapy in this patient collective. [ABSTRACT FROM AUTHOR]

المؤلفون: Manabu Taneike¹, Kazuhiko Nishida¹, Shigemiki Omiya¹, Zarrinpashneh, Elham¹, Tomofumi Misaka¹, Rika Kitazume-Taneike¹, Ruth Austin¹, Minoru Takaoka¹, Osamu Yamaguchi², Gambello, Michael J.³, Shah, Ajay M.¹, Kinya Otsu¹ kinya.otsu@kcl.ac.uk

المصدر: PLoS ONE. 3/29/2016, Vol. 11 Issue 3, p1-18. 18p.

مصطلحات موضوعية: *MTOR inhibitors, *TUBERIN, *HEART diseases, *DOWNREGULATION, *CELL proliferation

مستخلص: Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, proliferation and metabolism. mTORC1 regulates protein synthesis positively and autophagy negatively. Autophagy is amajor systemto manage bulk degradation and recycling of cytoplasmic components and organelles. Tuberous sclerosis complex (TSC) 1 and 2 form a heterodimeric complex and inactivate Ras homolog enriched in brain, resulting in inhibition of mTORC1. Here, we investigated the effects of hyperactivation of mTORC1 on cardiac function and structure using cardiac-specific TSC2-deficient (TSC2-/-) mice. TSC2-/- mice were born normally at the expected Mendelian ratio. However, the median life span of TSC2-/- mice was approximately 10 months and significantly shorter than that of control mice. TSC2-/-mice showed cardiac dysfunction and cardiomyocyte hypertrophy without considerable fibrosis, cell infiltration or apoptotic cardiomyocyte death. Ultrastructural analysis of TSC2-/- hearts revealed misalignment, aggregation and a decrease in the size and an increase in the number of mitochondria, but themitochondrial function wasmaintained. Autophagic flux was inhibited, while the phosphorylation level of S6 or eukaryotic initiation factor 4E -binding protein 1, downstream of mTORC1, was increased. The upregulation of autophagic flux by trehalose treatment attenuated the cardiac phenotypes such as cardiac dysfunction and structural abnormalities of mitochondria in TSC2-/- hearts. The results suggest that autophagy via the TSC2-mTORC1 signaling pathway plays an important role in maintenance of cardiac function and mitochondrial quantity and size in the heart and could be a therapeutic target to maintain mitochondrial homeostasis in failing hearts. [ABSTRACT FROM AUTHOR]

المؤلفون: Wolin, Edward, Mita, Alain, Mahipal, Amit, Meyer, Tim, Bendell, Johanna, Nemunaitis, John, Munster, Pam N., Paz-Ares, Luis, Filvaroff, Ellen H., Li, Shaoyi, Hege, Kristen, de Haan, Hans, Mita, Monica

المصدر: PLoS ONE; 9/17/2019, Vol. 14 Issue 9, p1-14, 14p

مصطلحات موضوعية: IRINOTECAN, NEUROENDOCRINE tumors, CARCINOID, KINASE inhibitors, PROGRESSION-free survival, MTOR inhibitors, AUTOPHAGY, EOSINOPHILIA

مستخلص: Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9–97.3%). Duration of PR was 125–401 days; median SD duration was 297 days (min–max, 50–1519 days). Median progression-free survival was 19.5 months (95% CI 10.4–28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development. [ABSTRACT FROM AUTHOR]

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المؤلفون: Oppermann, Henry, Faust, Helene, Yamanishi, Ulrike, Meixensberger, Jürgen, Gaunitz, Frank

المصدر: PLoS ONE; 6/27/2019, Vol. 14 Issue 6, p1-14, 14p

مصطلحات موضوعية: PYRUVATE dehydrogenase kinase, CARNOSINE, REPORTER genes, RAPAMYCIN, MTOR inhibitors, GENE expression

مستخلص: Glioblastoma is a high-grade glioma with poor prognosis even after surgery and standard therapy. Here, we asked whether carnosine (β-alanyl-L-histidine), a naturally occurring dipeptide, exert its anti-neoplastic effect on glioblastoma cells via PI3K/Akt/mTOR signaling. Therefore, glioblastoma cells from the lines U87 and T98G were exposed to carnosine, to the mTOR inhibitor rapamycin and to the PI3K inhibitor Ly-294,002. Pyruvate dehydrogenase kinase (PDK4) expression, known to be a target of PI3K/Akt/mTOR, and which is also affected by carnosine, was analyzed by RT-qPCR, and reporter gene assays with the human PDK4 promoter were performed. Cell viability was assessed by cell-based assays and mTOR and Akt phosphorylation by Western blotting. Rapamycin and Ly-294,002 increased PDK4 mRNA expression in both cell lines but significance was only reached in U87. Carnosine significantly increased expression in both lines. A significant combinatorial effect of carnosine was only detected in U87 when the dipeptide was combined with Ly-294,002. Reporter gene assays revealed no specific effect of carnosine on the human PDK4 promoter, whereas both inhibitors increased reporter gene expression. Rapamycin reduced phosphorylation of mTOR, and Ly-294,002 that of Akt. A significant reduction of Akt phosphorylation was observed in the presence of carnosine in U87 but not in T98G, and carnosine had no effect on mTOR phosphorylation. Cell viability as determined by ATP in cell lysates was reduced only in the presence of carnosine. We conclude that carnosine’s anti-neoplastic effect is independent from PI3K/Akt/mTOR signaling. As the dipeptide reduced viability in tumor cells that do not respond to PI3K or mTOR inhibitors, it appears to be worth to further investigate the mechanisms by which carnosine exerts its anti-tumor effect and to consider it for therapy, especially as it is a naturally occurring compound that has already been used for the treatment of other diseases without indication of side-effects. [ABSTRACT FROM AUTHOR]

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