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].
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.
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]。