Rapamycin (Sirolimus)
(Synonyms: 雷帕霉素; 西罗莫司; Sirolimus; AY-22989) 目录号 : GC15031
An allosteric inhibitor of mTORC1
Cas No.:53123-88-9
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| Cell experiment [1]: | |
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Cell lines |
HGF-Treated Lens Epithelial Cells (LECs) |
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Preparation Method |
After pretreatment with HGF for 12 h, LEC was treated with increased doses of rapamycin (0, 1.5 and 10 ng/mL) at different time points (24, 48 and 72 h). |
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Reaction Conditions |
1/5/10 ng/mL for 24/48h/72h |
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Applications |
Rapamycin inhibited the proliferation of lens epithelial cells (LEC) induced by hepatocyte growth factor (HGF) in a dose-and time-dependent manner. |
| Animal experiment [2]: | |
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Animal models |
Ndufs4 -- / -- mice |
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Preparation Method |
Rapamycin (8 mg/kg) was delivered by intraperitoneal injection every other day from weaning [approximately day 20 postpartum (P20)]. |
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Dosage form |
8 mg/kg, every other day, by intraperitoneal injection |
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Applications |
Rapamycin reduces neurologic disease in Ndufs4 -- / -- mice. |
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References: [1]: Tian F, Dong L, et,al. Rapamycin-Induced apoptosis in HGF-stimulated lens epithelial cells by AKT/mTOR, ERK and JAK2/STAT3 pathways. Int J Mol Sci. 2014 Aug 11;15(8):13833-48. doi: 10.3390/ijms150813833. PMID: 25116684; PMCID: PMC4159827. |
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Rapamycin used to be used as an antifungal antibiotic[3]. Rapamycin exerts immunosuppressive effects by inhibiting the activation and proliferation of T cells. Rapamycin binds to FK-binding protein 12 (FKBP12) to form the Rapamycin-FKBP12 complex, which can inhibit mTOR[4,6].As a potent and specific mTOR inhibitor with an IC50?of 0.1 nM in HEK293 cells. Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1[5].
Rapamycin (12.5-100 nM; 24 hours) treatment exerts modest inhibitory effect on lung cancer cell proliferation in a dose-dependent manner in all cell lines (A549, SPC-A-1, 95D and NCI-H446 cells) tested, achieving about 30-40% reduction in cell proliferation at 100 nM vs. ~10% reduction at 12.5 nM[7].Rapamycin potently not only suppressed proliferation but also induced the apoptosis of LECs in a dose-dependent manner under HGF administration. Rapamycin could promote apoptosis of LECs via inhibiting HGF-induced phosphorylation of AKT/mTOR, ERK and JAK2/STAT3 signaling molecules[1].
Rapamycin reduces neurologic disease in Ndufs4 -- / -- mice. In rapamycin treated knockout mice, the percentage of mice exhibiting neurological symptoms was greatly reduced at each age point after P35, and about half of these mice never showed obvious signs of neurological disease before dying[2]. Rapamycin alone has a moderate inhibitory effect. However, the combination of Metformin and Rapamycin exerts a significantly increased inhibition of tumor growth compared with the control group, the Rapamycin monotherapy group and the Metformin monotherapy group[8].Rapamycin treatment in cell culture significantly inhibits c-Myc-regulated gene expression. Rapamycin suppresses tumor growth along with a decreased expression of STAT3 and c-Myc in an in vivo xenograft mouse model for hepatocellular carcinoma[9].
Rapamycin曾经被用作抗真菌抗生素。它通过抑制T细胞的激活和增殖来发挥免疫抑制作用。Rapamycin结合FK结合蛋白12（FKBP12）形成Rapamycin-FKBP12复合物，可以抑制mTOR。在HEK293细胞中，Rapamycin是一种有效而特异性的mTOR抑制剂，其IC50为0.1 nM。Rapamycin结合FKBP12并特异性地作为mTORC1的变构抑制剂。
在所有测试的细胞系（A549、SPC-A-1、95D和NCI-H446细胞）中，拉帕霉素（12.5-100 nM；24小时）治疗以剂量依赖性方式对肺癌细胞增殖产生适度的抑制作用，在100 nM时实现约30-40%的细胞增殖减少，而在12.5 nM时仅有约10%的减少。拉帕霉素不仅能有效地抑制增殖，还能以剂量依赖性方式诱导LEC的凋亡，在HGF管理下通过抑制AKT/mTOR、ERK和JAK2/STAT3信号分子的磷酸化来促进LEC的凋亡。
在Ndufs4 - / -小鼠中，雷帕霉素减少了神经疾病。在接受雷帕霉素治疗的敲除小鼠中，在P35后的每个年龄点上表现出神经症状的小鼠比例大大降低，并且其中约有一半的小鼠在死亡前从未显示出明显的神经疾病迹象[2]。单用雷帕霉素具有适度抑制作用。然而，二甲双胍和雷帕霉素联合使用与对照组、单用雷帕霉素组和单用二甲双胍组相比，能够显著增强肿瘤生长的抑制作用[8]。细胞培养中使用雷帕霉素可显著抑制c-Myc调节基因表达。在体内移植模型下，雷帕霉素通过降低STAT3和c-Myc表达来抑制肝细胞癌肿瘤生长[9]。
References:
[1]: Tian F, Dong L, et,al. Rapamycin-Induced apoptosis in HGF-stimulated lens epithelial cells by AKT/mTOR, ERK and JAK2/STAT3 pathways. Int J Mol Sci. 2014 Aug 11;15(8):13833-48. doi: 10.3390/ijms150813833. PMID: 25116684; PMCID: PMC4159827.
[2]: Johnson SC, Yanos ME, et,al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science. 2013 Dec 20;342(6165):1524-8. doi: 10.1126/science.1244360. Epub 2013 Nov 14. PMID: 24231806; PMCID: PMC4055856.
[3]: Sehgal SN, Baker H, et,al. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo). 1975 Oct;28(10):727-32. doi: 10.7164/antibiotics.28.727. PMID: 1102509.
[4]: Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 1998 Jul;31(5):335-40. doi: 10.1016/s0009-9120(98)00045-9. PMID: 9721431.
[5]: Edwards SR, Wandless TJ. The rapamycin-binding domain of the protein kinase mammalian target of rapamycin is a destabilizing domain. J Biol Chem. 2007 May 4;282(18):13395-401. doi: 10.1074/jbc.M700498200. Epub 2007 Mar 9. PMID: 17350953; PMCID: PMC3763840.
[6]: Rangaraju S, Verrier JD, et,al. Rapamycin activates autophagy and improves myelination in explant cultures from neuropathic mice. J Neurosci. 2010 Aug 25;30(34):11388-97. doi: 10.1523/JNEUROSCI.1356-10.2010. PMID: 20739560; PMCID: PMC3478092.
[7]: Niu H, Wang J, et,al. Rapamycin potentiates cytotoxicity by docetaxel possibly through downregulation of Survivin in lung cancer cells. J Exp Clin Cancer Res. 2011 Mar 10;30(1):28. doi: 10.1186/1756-9966-30-28. PMID: 21392382; PMCID: PMC3065416.
[8]: Zhang JW, Zhao F, et,al. Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer in vitro and in vivo. Oncol Lett. 2018 Feb;15(2):1811-1816. doi: 10.3892/ol.2017.7444. Epub 2017 Nov 20. PMID: 29434877; PMCID: PMC5774390.
[9]: Sun L, Yan Y, et,al. Rapamycin targets STAT3 and impacts c-Myc to suppress tumor growth. Cell Chem Biol. 2022 Mar 17;29(3):373-385.e6. doi: 10.1016/j.chembiol.2021.10.006. Epub 2021 Oct 26. PMID: 34706270.
| Cas No. | 53123-88-9 | SDF | |
| 别名 | 雷帕霉素; 西罗莫司; Sirolimus; AY-22989 | ||
| Canonical SMILES | O[C@H]1[C@H](OC)C[C@H](C[C@@H](C)[C@H](CC([C@H](C)/C=C(C)/[C@H]([C@@H](OC)C([C@@H](C[C@@H](/C=C/C=C/C=C(C)/[C@@H](OC)C[C@@H]2CC[C@@H](C)[C@@](C(C(N3[C@H]4CCCC3)=O)=O)(O)O2)C)C)=O)O)=O)OC4=O)CC1 | ||
| 分子式 | C51H79NO13 | 分子量 | 914.18 |
| 溶解度 | ≥ 45.709mg/mL in DMSO, ≥ 58.9 mg/mL in EtOH with ultrasonic | 储存条件 | Desiccate at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.0939 mL | 5.4694 mL | 10.9388 mL |
| 5 mM | 0.2188 mL | 1.0939 mL | 2.1878 mL |
| 10 mM | 0.1094 mL | 0.5469 mL | 1.0939 mL |
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Rapamycin for longevity: opinion article
From the dawn of civilization, humanity has dreamed of immortality. So why didn't the discovery of the anti-aging properties of mTOR inhibitors change the world forever? I will discuss several reasons, including fear of the actual and fictional side effects of rapamycin, everolimus and other clinically-approved drugs, arguing that no real side effects preclude their use as anti-aging drugs today. Furthermore, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging: cancer, stroke, infarction, blindness and premature death. I will also discuss why it is more dangerous not to use anti-aging drugs than to use them and how rapamycin-based drug combinations have already been implemented for potential life extension in humans. If you read this article from the very beginning to its end, you may realize that the time is now.
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.
Clinical pharmacokinetics of everolimus
Everolimus is an immunosuppressive macrolide bearing a stable 2-hydroxyethyl chain substitution at position 40 on the sirolimus (rapamycin) structure. Everolimus, which has greater polarity than sirolimus, was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase its oral bioavailability. Everolimus has a mechanism of action similar to that of sirolimus. It blocks growth-driven transduction signals in the T-cell response to alloantigen and thus acts at a later stage than the calcineurin inhibitors ciclosporin and tacrolimus. Everolimus and ciclosporin show synergism in immunosuppression both in vitro and in vivo and therefore the drugs are intended to be given in combination after solid organ transplantation. The synergistic effect allows a dosage reduction that decreases adverse effects. For the quantification of the pharmacokinetics of everolimus, nine different assays using high performance liquid chromatography coupled to an electrospray mass spectrometer, and one enzyme-linked immunosorbent assay, have been developed. Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3-1.8 hours. Steady state is reached within 7 days, and steady-state peak and trough concentrations, and area under the concentration-time curve (AUC), are proportional to dosage. In adults, everolimus pharmacokinetic characteristics do not differ according to age, weight or sex, but bodyweight-adjusted dosages are necessary in children. The interindividual pharmacokinetic variability of everolimus can be explained by different activities of the drug efflux pump P-glycoprotein and of metabolism by cytochrome P450 (CYP) 3A4, 3A5 and 2C8. The critical role of the CYP3A4 system for everolimus biotransformation leads to drug-drug interactions with other drugs metabolised by this cytochrome system. In patients with hepatic impairment, the apparent clearance of everolimus is significantly lower than in healthy volunteers, and therefore the dosage of everolimus should be reduced by half in these patients. The advantage of everolimus seems to be its lower nephrotoxicity in comparison with the standard immunosuppressants ciclosporin and tacrolimus. Observed adverse effects with everolimus include hypertriglyceridaemia, hypercholesterolaemia, opportunistic infections, thrombocytopenia and leucocytopenia. Because of the variable oral bioavailability and narrow therapeutic index of everolimus, blood concentration monitoring seems to be important. The excellent correlation between steady-state trough concentration and AUC makes the former a simple and reliable index for monitoring everolimus exposure. The target trough concentration of everolimus should range between 3 and 15 microg/L in combination therapy with ciclosporin (trough concentration 100-300 microg/L) and prednisone.
Sirolimus (rapamycin): from the soil of Easter Island to a bright future
Discovered in fungi in the remote Easter Island, sirolimus (rapamycin) shows potential beyond its obvious antiproliferative and immunosuppressant activity. Studies have demonstrated that sirolimus acts as a vascular endothelial growth factor inhibitor, providing prospective therapeutic benefits and possible prevention of tuberous sclerosis and Kaposi's sarcoma. Its ability to decrease keratinocyte proliferation may help patients with psoriasis. In those with tuberous sclerosis complex, it may prevent the development of hamartomas and reduce or eliminate them once grown by blocking the mammalian target of rapamycin, a critical regulatory kinase. A great advantage for this drug is in the decreased risk of malignancies, including Kaposi's sarcoma, associated with its use compared with other immunosuppressants, namely calcineurin inhibitors. This review will focus on the pharmacology and potential uses of sirolimus.
Efficacy of sirolimus in children with lymphatic malformations of the head and neck
Purpose: Children with extensive lymphatic malformations of the head and neck often suffer from functional impairment and aesthetic deformity which significantly affect the quality of life and may be life-threatening. Treatment with sirolimus has the potential to improve symptoms and downsize lymphatic malformations. This systematic review summarizes the current information about sirolimus treatment of lymphatic malformations of the head and neck in children, its efficacy and side effects.
Methods: A systematic search of the literature regarding studies on sirolimus treatment of children with lymphatic malformations of the head and neck was performed in PubMed, Embase, and Google Scholar up to July 2021 with the search terms "lymphatic malformation", "lymphangioma", "cystic hygroma", "low-flow malformation", "sirolimus", "rapamycin", "mTOR inhibitor" and "children".
Results: In all, 28 studies including 105 children from newborn to 17 years treated with sirolimus for lymphatic malformations of the head and neck were analyzed. The most frequent initial dose was 0.8 mg/m2 per dose, twice daily at 12-h interval. The target blood level differed between studies, 10-15 ng/mL and 5-15 ng/mL were most often used. More than 91% of the children responded to sirolimus treatment which lasts from 6 months to 4 years. Typical side effects were hyperlipidemia, neutropenia and infections.
Methods: Sirolimus could be an effective treatment for children with large complicated lymphatic malformations of the head and neck. As not all patients will benefit from treatment, the decision to treat sirolimus should be made by a multidisciplinary team.