Title | Abstract | NumberCitations | Date | Authors | LinkToPaper |
Effect of rapamycin on aging and age-related diseases—past and future | In 2009, rapamycin was reported to increase the lifespan of mice when implemented later in life. This observation resulted in a sea-change in how researchers viewed aging. This was the first evidence that a pharmacological agent could have an impact on aging when administered later in life, i.e., an intervention that did not have to be implemented early in life before the negative impact of aging. Over the past decade, there has been an explosion in the number of reports studying the effect of rapamycin on various diseases, physiological functions, and biochemical processes in mice. In this review, we focus on those areas in which there is strong evidence for rapamycin’s effect on aging and age-related diseases in mice, e.g., lifespan, cardiac disease/function, central nervous system, immune system, and cell senescence. We conclude that it is time that pre-clinical studies be focused on taking rapamycin to the clinic, e.g., as a potential treatment for Alzheimer’s disease. | 14 | 10 October 2020 | Ramasamy Selvarani, Sabira Mohammed & Arlan Richardson | https://link.springer.com/article/10.1007/s11357-020-00274-1 |
A novel rapamycin analog is highly selective for mTORC1 in vivo | Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs. | 53 | 19 July 2019 | Katherine H. Schreiber, Sebastian I. Arriola Apelo, Deyang Yu, Jacqueline A. Brinkman, Michael C. Velarde, Faizan A. Syed, Chen-Yu Liao, Emma L. Baar, Kathryn A. Carbajal, Dawn S. Sherman, Denise Ortiz, Regina Brunauer, Shany E. Yang, Stelios T. Tzannis, Brian K. Kennedy & Dudley W. Lamming | https://www.nature.com/articles/s41467-019-11174-0 |
Rapamycin: Current and Future Uses | The mTOR inhibitor rapamycin has received growing attention due to its immunosuppresive, antineoplastic and lifespan extending properties. The discovery of the drug and its target has had widespread implications for our under-standing of the underlying metabolic processes in the cell. Indeed, rapamycin has opened up a new field of potential pharmacological targets. In the following chapter I will briefly review the molecular target of rapamycin and the current clinical applications for this compound | 69 | November 2013 | Morten Scheibye-Knudsen | https://www.researchgate.net/publication/263655002_Rapamycin_Current_and_Future_Uses |
Chemistry and Pharmacology of Rapamycin and Its Derivatives | Rapamycin is a bacterially derived natural product with a remarkable history as both a chemical probe for studies of cell growth control-related pathways, and a bona fide drug with established or predicted clinical activities in a variety of disease settings. Rapamycin was first noted as a potent antifungal and immunosuppressive agent, and studies of this drug's mechanism of action revealed that rapamycin was a surgically precise inhibitor of a novel protein serine-threonine kinase, appropriately termed the target of rapamycin (TOR). Intensive research efforts have revealed that the TOR orthologs function in a highly conserved pathway of eukaryotic cell growth control. This review focuses on the impact of rapamycin exposure on the TOR ortholog (termed mTOR) expressed in mammalian cells. We briefly describe the biosynthesis of rapamycin and the chemical modifications of the parent compound that yielded several of the experimentally useful and/or clinically active derivatives, collectively termed rapalogs. We then review in some detail the pharmacology of rapamycin, particularly as it relates to the growth and proliferation of cancer cells. The opportunities and challenges associated with the development of rapalogs as anticancer agents are then discussed. Finally, we briefly review some provocative recent insights into the effects of rapamycin on the immune system and on organismal aging. | 9 | December 2010 | Robert T. Abraham, James J. Gibbons | https://www.researchgate.net/publication/251471605_Chemistry_and_Pharmacology_of_Rapamycin_and_Its_Derivatives |
An overview of rapamycin: from discovery to future perspectives | 45 | September 2016 | Young Ji Yoo, Hanseong Kim, Sung Ryeol Park, Yeo Joon Yoon | https://www.researchgate.net/publication/307978898_An_overview_of_rapamycin_from_discovery_to_future_perspectives | |
The Molecular Target of Rapamycin (mTOR) as a Therapeutic Target Against Cancer | The molecular target of rapamycin (mTOR), which is a member of the phosphoinositide3-kinase related kinase (PIKK) family and a central modulator of cell growth, is a primestrategic target for anti-cancer therapeutic development. mTOR plays a critical role intransducing proliferative signals mediated through the phosphatidylinositol 3 kinase(PI3K)/protein kinase B (Akt) signaling pathway, principally by activating downstreamprotein kinases that are required for both ribosomal biosynthesis and translation of keymRNAs of proteins required for G1to S phase traverse. By targeting mTOR, the immun-suppressant and antiproliferative agent rapamycin (RAP) inhibits signals required for cellcycle progression, cell growth, and proliferation.RAP, a complex macrolide and highly potent fungicide, immunosuppressant, andanti-cancer agent, is a highly specific inhibitor of mTOR. In essence, RAP gains functionby binding to the immunophilin FK506 binding protein 12 (FKBP12) and the resultantcomplex inhibits the activity of mTOR. Since mTOR activates both the 40S ribosomalprotein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1(4E-BP1), RAP blocks activation of these downstream signaling elements, which results incell cycle arrest in the G1arrest. RAP also prevents cyclin-dependent kinase (cdk) activation,inhibits retinoblastoma protein (pRb) phosphorylation, and accelerates the turnover ofcyclin D1 that leads to a deficienciy of active cdk4/cyclin D1 complexes, all of whichpotentially contribute to the prominent inhibitory effects of RAP at the G1/S phase transition.Both RAP and several RAP analogs with more favorable pharmaceutical properties havedemonstrated prominent growth inhibitory effects against a broad range of human cancersin both preclinical and early clinical evaluations.This review will summarize the principal mechanisms of action of RAP and RAP deriv-atives and their potential utility of these agents as anti-cancer therapeutics. The preliminaryresults of early clinical evaluations with RAP analogs and the unique developmentalchallenges that lie ahead will also be discussed | 161 | July 2003 | Monica M Mita, Alain Mita, Eric Rowinsky | https://www.researchgate.net/publication/9081889_The_Molecular_Target_of_Rapamycin_mTOR_as_a_Therapeutic_Target_Against_Cancer |
Is rapamycin a rapalog? | 2 | July 2018 | David J. Glass, Dudley William Lamming | https://www.researchgate.net/publication/326237605_Is_rapamycin_a_rapalog | |
Bioprocess Engineering Aspects of Rapamycin (Sirolimus) Production: A Review on Past Achievements and Recent Perspectives | In recent times, immunosuppressants are receiving considerable popularity day by day for its significant contribution in medical field and consequently in the world market. Rapamycin (sirolimus) is a potent immunosuppressant which has antifungal, anti-aging, neuroprotective, anti-tumor activities. Rapamycin is produced by many strains of Streptomyces hygroscopicus by submerged fermentation technique. Inadequate amount of the drug synthesized by the species leads to a great challenge to the engineers for further development and industrialization of this important polyketide. Therefore, an in-depth study with respect to bioprocess engineering aspects is required for enhanced production of this important antibiotic. In this review, various bioengineering aspects of industrial production of this metabolite viz., metabolic engineering, optimization, strain improvement strategies and kinetics studies have been discussed. | 5 | December 2014 | Subhashish Dutta, Bikram Basak, Biswanath Bhunia, Apurba Dey | https://www.researchgate.net/publication/281591148_Bioprocess_Engineering_Aspects_of_Rapamycin_Sirolimus_Production_A_Review_on_Past_Achievements_and_Recent_Perspectives |
Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB | The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a multiprotein complex composed of mTOR, mLST8, and raptor (mTORC1). The distinct complex of mTOR, mLST8, and rictor (mTORC2) does not interact with FKBP12-rapamycin and is not thought to be rapamycin sensitive. mTORC2 phosphorylates and activates Akt/PKB, a key regulator of cell survival. Here we show that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolonged rapamycin treatment reduces the levels of mTORC2 below those needed to maintain Akt/PKB signaling. The proapoptotic and antitumor effects of rapamycin are suppressed in cells expressing an Akt/PKB mutant that is rapamycin resistant. Our work describes an unforeseen mechanism of action for rapamycin that suggests it can be used to inhibit Akt/PKB in certain cell types. | 2283 | May 2006 | Dos D Sarbassov, Siraj M. Ali, Shomit Sengupta, Joon-Ho Sheen, Peggy P Hsu, Alex F Bagley, Andrew L Markhard, David M Sabatini | https://www.researchgate.net/publication/7177234_Prolonged_rapamycin_treatment_inhibits_mTORC2_assembly_and_AktPKB |
Current Update on Rapamycin Production and its Potential Clinical Implications | 76 | March 2019 | Girijesh K Patel, Ruchika Goyal, Syed Mohsin Waheed | https://www.researchgate.net/publication/331806121_Current_Update_on_Rapamycin_Production_and_its_Potential_Clinical_Implications | |
Rapamycin treatment inhibits CHO cell death in a serum-free suspension culture by autophagy induction | Rapamycin, a specific mTOR inhibitor, has been used as a chemical activator in autophagy research both in vitro and in vivo. Recently, autophagy has received attention as an anti-cell death engineering target in addition to apoptosis in the Chinese hamster ovary (CHO) cell engineering field. Here, the effect of rapamycin and the subsequent autophagy induction is investigated on two CHO cell lines, DG44 host and an antibody-producing recombinant CHO (rCHO), in a serum-free suspension culture. In both cell lines, the rapamycin treatment delayed the viability drop and apoptosis induction. In particular, the improved cell viability of the antibody-producing rCHO cell line resulting from the rapamycin treatment led to a 21% increase in the maximum antibody concentration. From observations that a rapamycin derivative, everolimus, demonstrated similar positive effects in both cell lines, but not FK-506, which forms the same complex as rapamycin, but does not inhibit mTOR, it was demonstrated that the positive effects of rapamycin appear to be mTOR-dependent. In addition, the cultivation with rapamycin and/or an autophagy inhibitor, bafilomycin A1, indicated that the autophagy induction is related to the positive effects of rapamycin. The genetic perturbation of the autophagy pathway through the regulation of the expression level of Beclin-1, an important autophagy regulator, resulted in a delayed autophagy induction and apoptosis inhibition in response to the rapamycin treatment in the DG44 host cell line. Taken together, the results obtained in this study imply a positive role for autophagy and predict the usefulness of pro-autophagy engineering in CHO cell cultures. Biotechnol. Bioeng. © 2012 Wiley Periodicals, Inc. | 31 | December 2012 | Jae Seong Lee, Gyun Min Lee | https://www.researchgate.net/publication/225043844_Rapamycin_treatment_inhibits_CHO_cell_death_in_a_serum-free_suspension_culture_by_autophagy_induction |
Rapamycin-Mediated Lifespan Increase in Mice is Dose and Sex-Dependent and Appears Metabolically Distinct from Dietary Restriction | Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females) when tested at a dose three-fold higher than that used in our previous studies; maximal longevity was also increased in both sexes. Rapamycin increased lifespan more in females than in males at each dose evaluated, perhaps reflecting sexual dimorphism in blood levels of this drug. Some of the endocrine and metabolic changes seen in diet-restricted mice are not seen in mice exposed to rapamycin, and the pattern of expression of hepatic genes involved in xenobiotic metabolism is also quite distinct in rapamycin-treated and diet restricted mice, suggesting that these two interventions for extending mouse lifespan differ in many respects. This article is protected by copyright. All rights reserved. | 350 | December 2013 | Richard A Miller, David E Harrison, Clinton M Astle, Elizabeth Fernandez, Kevin Flurkey, Melissa Han, ,Martin A Javors, Xinna Li, Nancy L Nadon, James F Nelson, Scott Pletcher, Adam B Salmon, Zelton Dave Sharp, Sabrina Van Roekel, Lynn Winkleman, Randy Strong | https://www.researchgate.net/publication/259348303_Rapamycin-Mediated_Lifespan_Increase_in_Mice_is_Dose_and_Sex-Dependent_and_Appears_Metabolically_Distinct_from_Dietary_Restriction |
Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways | Numerous studies have shown that mammalian target of rapamycin (mTOR) inhibitor activates Akt signaling pathway via a negative feedback loop while inhibiting mTORC1 signaling. In this report, we focused on studying the role of mTORC1 and mTORC2 in rapamycin-mediated Akt and ERK phosphorylation, and the antitumor effect of rapamycin in cancer cells in combination with Akt and ERK inhibitors. Moreover, we analyzed the effect of mTORC1 and mTORC2 on regulating cell cycle progression. We found that low concentrations rapamycin increased Akt and ERK phosphorylation through a mTORC1-dependent mechanism because knockdowned raptor induced the activation of Akt and ERK, but higher doses of rapamycin inhibited Akt and ERK phosphorylation mainly via the mTORC2 signaling pathway because that the silencing of rictor led to the inhibition of Akt and ERK phosphorylation. We further showed that mTORC2 was tightly associated with the development of cell cycle through an Akt-dependent mechanism. Therefore, we combined PI3K and ERK inhibitors prevent rapamycin-induced Akt activation and enhanced antitumor effects of rapamycin. Collectively, we conclude that mTORC2 plays a much more important role than mTORC1 in rapamycin-mediated phosphorylation of Akt and ERK, and cotargeting AKT and ERK signaling may be a new strategy for enhancing the efficacy of rapamycin-based therapeutic approaches in cancer cells. | 72 | June 2010 | Xian-Guo Chen, Fei Liu, Xing-Fu Song, Zhi-Hua Wang, Zi-Qiang Dong, Zhi-Quan Hu, Ru-Zhu Lan, Wei Guan, Tian-Gui Zhou, Xiao-Ming Xu, Hong Lei, Zhang-Qun Ye, E-Jun Peng, Li-Huan Du, Qian-Yuan Zhuang | https://www.researchgate.net/publication/44640017_Rapamycin_regulates_Akt_and_ERK_phosphorylation_through_mTORC1_and_mTORC2_signaling_pathways |
Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue | Complexed with its intracellular receptor, FKBP12, the natural product rapamycin inhibits G1 progression of the cell cycle in a variety of mammalian cell lines and in the yeast Saccharomyces cerevisae. Previously, a mammalian protein that directly associates with FKBP12-rapamycin has been identified and its encoding gene has been cloned from both human (designated FRAP) [Brown, E.J., Albers, M.W., Shin, T.B., Ichikawa, K., Keith, C.T., Lane, W.S. & Schreiber, S.L. (1994) Nature (London) 369, 756-758] and rat (designated RAFT) [Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S.H. (1994) Cell 78, 35-43]. The full-length FRAP is a 289-kDa protein containing a putative phosphatidylinositol kinase domain. Using an in vitro transcription/translation assay method coupled with proteolysis studies, we have identified an 11-kDa FKBP12-rapamycin-binding domain within FRAP. This minimal binding domain lies N-terminal to the kinase domain and spans residues 2025-2114. In addition, we have carried out mutagenesis studies to investigate the role of Ser2035, a potential phosphorylation site for protein kinase C within this domain. We now show that the FRAP Ser2035-->Ala mutant displays similar binding affinity when compared with the wild-type protein, whereas all other mutations at this site, including mimics of phosphoserine, abolish binding, presumably due to either unfavorable steric interactions or induced conformational changes. | 478 | June 1995 | Jie Chen, X.F. Zheng, E.J. Brown, S.L. Schreiber | https://www.researchgate.net/publication/15660250_Identification_of_an_11-kDa_FKBP12-rapamycin-binding_domain_within_the_289-kDa_FKBP12-rapamycin-associated_protein_and_characterization_of_a_critical_serine_residue |
Rapamycin: An anti-cancer immunosuppressant? | Rapamycin and its derivatives are promising therapeutic agents with both immunosuppressant and anti-tumor properties. These rapamycin actions are mediated through the specific inhibition of the mTOR protein kinase. mTOR serves as part of an evolutionarily conserved signaling pathway that controls the cell cycle in response to changing nutrient levels. The mTOR signaling network contains a number of tumor suppressor genes including PTEN, LKB1, TSC1, and TSC2, and a number of proto-oncogenes including PI3K, Akt, and eIF4E, and mTOR signaling is constitutively activated in many tumor types. These observations point to mTOR as an ideal target for anti-cancer agents and suggest that rapamycin is such an agent. In fact, early preclinical and clinical studies indicate that rapamycin derivatives have efficacy as anti-tumor agents both alone, and when combined with other modes of therapy. Rapamycin appears to inhibit tumor growth by halting tumor cell proliferation, inducing tumor cell apoptosis, and suppressing tumor angiogenesis. Rapamycin immunosuppressant actions result from the inhibition of T and B cell proliferation through the same mechanisms that rapamycin blocks cancer cell proliferation. Therefore, one might think that rapamycin-induced immunosuppression would be detrimental to the use of rapamycin as an anti-cancer agent. To the contrary, rapamycin decreases the frequency of tumor formation that occurs in organ transplant experiments when combined with the widely used immunosuppressant cyclosporine compared with the tumor incidence observed when cyclosporine is used alone. The available evidence indicates that with respect to tumor growth, rapamycin anti-cancer activities are dominant over rapamycin immunosuppressant effects. | 210 | November 2005 | Brian Law | https://www.researchgate.net/publication/7705387_Rapamycin_An_anti-cancer_immunosuppressant |
Efficacy of rapamycin in patient with juvenile rheumatoid arthritis | Juvenile rheumatoid arthritis (JRA) is an immune-mediated disease characterized by articular inflammation and subsequent tissue damage that may result in severe disability. Several combinations of drugs, including immunosuppressive agents have been used to control disease progression. Although there is no information available on rapamycin efficacy in JRA, it has demonstrated a potential to inhibit inflammatory processes observed in adult rheumatoid arthritis (RA). We present a 21 years old renal transplant recipient with JRA, primarily treated with tacrolimus and steroids, who achieved a long-term disease remission after introduction of rapamycin. As long as pathogenesis of JRA and RA is similar, we conclude that rapamycin could be promising immunosuppressant for patients after renal transplantation suffering from both JRA and RA. | 28 | April 2005 | Bartosz Foroncewicz, Krzysztof Mucha, Leszek Paczek, Andrzej Chmura | https://www.researchgate.net/publication/8002186_Efficacy_of_rapamycin_in_patient_with_juvenile_rheumatoid_arthritis |
Toxicity spectrum of inhibitors of mammalian target of rapamycin in organ transplantation: Etiology, pathogenesis and treatment | Introduction: Control of the immune responses is critical for body homeostasis. Immunosuppressive strategies have been critical to this enterprise as they reveal molecular and cellular mechanisms of immune-mediated tissue destruction. Areas covered: While exerting potent effects to blockade critical processes during cell maturation prior to division and effector functions, the novel drug class of mammalian target of rapamycin inhibitors (mTORi) consequently exert adverse reactions due to disruption of pleiotropic physiologic pathways. This review includes selected clinical and preclinical materials from the time of the author's own first-in-human experience in 1993 through to 2009. The goal of this contribution is to provide a foundation in basic biochemical processes to allow the reader to understand the pathophysiology of adverse clinical reactions. Expert opinion: mTORi, as potent agents for clinical immunosuppression, inevitably, disrupt multiple cellular pathways as well as important vectors of host resistance. Judicious use of this pharmacologic class demands dedication to learning strategies of individualization for patient needs and reactions in the manner of clinicians previously committed on the introduction of calcineurin inhibitors 3 decades ago. | 18 | May 2011 | Barry Kahan | https://www.researchgate.net/publication/51112821_Toxicity_spectrum_of_inhibitors_of_mammalian_target_of_rapamycin_in_organ_transplantation_Etiology_pathogenesis_and_treatment |
Rapamycin in mice | 13 | September 2017 | William R. Swindell | https://www.researchgate.net/publication/319445429_Rapamycin_in_mice | |
Rapamycin: one drug, many effects | The mammalian target of rapamycin (mTOR) signaling pathway is a master regulator of cell growth and metabolism. Deregulation of the mTOR pathway has been implicated in a number of human diseases such as cancer, diabetes, obesity, neurological diseases and genetic disorders. Rapamycin, a specific inhibitor of mTOR, has been shown to be useful in the treatment of certain diseases. Here we discuss its mechanism of action and highlight recent findings regarding the effects and limitations of rapamycin monotherapy and the potential utility of combination therapy with rapamycin. | 2014 Feb 6 | Jing Li, Sang Gyun Kim, and John Blenis | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972801/ |