专家论坛

雷公藤红素与肿瘤代谢的关系研究进展

  • 李晔 ,
  • 宋蒙蒙 ,
  • 常文军 ,
  • 缪明永 ,
  • 潘亚敏
展开
  • 1上海中医药大学附属曙光医院内镜中心,上海 201203;2 郑州大学公共卫生学院流行病学教研室,郑州450052;3 第二军医大学热带医学与公共卫生学系环境卫生教研室,上海 200433;4 第二军医大学基础医学部生物化学与分子生物学教研室,上海 200433

网络出版日期: 2021-04-12

基金资助

国家自然科学基金(81774079)

Research progress on the relationship between celastrol and tumor metabolism

  • Li Ye ,
  • Song Mengmeng ,
  • Chang Wenjun ,
  • Miao Mingyong ,
  • Pan Yamin
Expand
  • 1Endoscopy center, Shuguang Hospital affiliated to Shanghai University of traditional Chinese Medicine, Shanghai 201203, China; 2Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450002,Henan, China; 3Department of Environmental Health, Second Military Medical University, Shanghai 200433,China; 4Department of Biochemistry and Molecular Biology, The College of Basic Medical Sciences, The Second Military Medical University, Shanghai 200433, China

Online published: 2021-04-12

摘要

雷公藤红素是一种中草药活性成分,具有广泛的治疗特性及较高的药用价值,通常用于治疗自身免疫性疾病、代谢性疾病及肿瘤。雷公藤红素可以通过多种途径抑制肿瘤的发生、发展,尤其与肿瘤代谢密切相关,对肿瘤细胞的糖代谢、脂类代谢、氨基酸代谢及肿瘤微环境产生重要影响。雷公藤红素导致线粒体功能障碍以改变葡萄糖代谢途径,使肿瘤细胞供能不足;通过诱导肝内Sirt1的表达影响肿瘤宿主的脂类代谢;抑制吲哚胺2,3双加氧酶(IDO)表达和色氨酸分解代谢来抑制结直肠癌,与IDO的抑制剂D-1MT联用控制胰腺癌;在肿瘤微环境中,雷公藤红素可通过抑制NLRP3炎性小体及重塑免疫抑制治疗黑色素瘤。根据最新研究报道,肠道菌群的高度代谢可以提高雷公藤红素在体内的功效,影响肿瘤发展。本文从代谢的角度阐述雷公藤红素对肿瘤的主要作用及机制,为其药理作用的深入研究提供科学依据。

本文引用格式

李晔 , 宋蒙蒙 , 常文军 , 缪明永 , 潘亚敏 . 雷公藤红素与肿瘤代谢的关系研究进展[J]. 肿瘤代谢与营养电子杂志, 2020 , 7(1) : 18 -21 . DOI: 10.16689/j.cnki.cn11-9349/r.2020.01.004

Abstract

Celastrol is an active ingredient of Chinese herbal medicine with extensive therapeutic properties and high medicinal value. It is commonly used in the treatment of autoimmune diseases, metabolic diseases and cancer. Celastrol can inhibit the occurrence and development of tumor through a variety of ways, especially closely related to tumor metabolism, and has an important impact on the metabolism of sugar metabolism, lipid metabolism, amino acid metabolism and tumor microenvironment of tumor cells. Celastrol causes mitochondrial dysfunction to alter the glucose metabolism pathway, resulting in insufficient energy supply to tumor cells; affects lipid metabolism in tumor hosts by inducing liver Sirt1 expression; inhibits the progress of colorectal cancer by inhibiting indoleamine 2,3 dioxygenase (IDO) expression and tryptophan catabolism, controls pancreatic cancer by combining with IDO inhibitor D-1MT. In the tumor microenvironment, celastrol can treat melanoma by inhibiting NLRP3 inflammatory bodies and remodeling immunosuppression. According to the latest research, the high metabolism of intestinal flora can improve the efficacy of celastrol in the body, affecting the development of tumors. This review describes the main effects and mechanisms of celastrol on tumors from a metabolic perspective, providing a scientific basis for its in-depth study of pharmacological effects.

参考文献

1.Kannaiyan R, Shanmugam MK, Sethi G. Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer. Cancer Lett. 2011;303(1):9-20.
2.Kuchta K, Xiang Y, Huang S, et al. Celastrol, an active constituent of the TCM plant Tripterygium wilfordii Hook.f., inhibits prostate cancer bone metastasis. Prostate Cancer Prostatic Dis. 2017;20(2):156-164.
3.Liu X, Zhao P, Wang X, et al. Celastrol mediates autophagy and apoptosis via the ROS/JNK and Akt/mTOR signaling pathways in glioma cells. J Exp Clin Cancer Res. 2019;38(1):184-186.
4.Yao SS, Han L, Tian ZB, et al. Celastrol inhibits growth and metastasis of human gastric cancer cell MKN45 by down-regulating microRNA-21. Phytother Res. 2019;33(6):1706-1716.
5.Gao Y, Zhou S, Pang L, et al. Celastrol suppresses nitric oxide synthases and the angiogenesis pathway in colorectal cancer. Free Radic Res. 2019;53(3):324-334.
6.Lin L, Sun Y, Wang D, et al. Celastrol ameliorates ulcerative colitis-related colorectal cancer in mice via suppressing inflammatory responses and epithelial-mesenchymal transition. Front Pharmacol. 2015;6:320.
7.Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
8.Koppenol WH, Bounds PL, Dang CV. Otto Warburgs contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11(5):325-337.
9.Li J, Huang Q, Long X, et al. Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress. Oncogene. 2017;36(34):4901-4912.
10.Hu Y, Qi Y, Liu H, et al. Effects of celastrol on human cervical cancer cells as revealed by ion-trap gas chromatography-mass spectrometry based metabolic profiling. Biochim Biophys Acta. 2013;1830(3):2779-2789.
11.Abu Bakar MH, Tan JS. Improvement of mitochondrial function by celastrol in palmitate-treated C2C12 myotubes via activation of PI3K-Akt signaling pathway. Biomed Pharmacother. 2017;93(2):903-912.
12.Abu Bakar MH, Sarmidi MR, Tan JS, et al. Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes. Eur J Pharmacol. 2017;799(1):73-83.
13.Kim JE, Lee MH, Nam DH, et al. Celastrol, an NF-kappaB inhibitor, improves insulin resistance and attenuates renal injury in db/db mice. PLoS One. 2013;8(4):e62068.
14.Han LP, Li CJ, Sun B, et al. Protective effects of celastrol on diabetic liver injury via TLR4/MyD88/NF-kappaB signaling pathway in Type 2 diabetic rats. J Diabetes Res. 2016;2016:2641248.
15.Grant CW, Moran-Paul CM, Duclos SK, et al. Testing agents for prevention or reversal of type 1 diabetes in rodents. PLoS One. 2013;8(8):e72989.
16.Pascual G, Avgustinova A, Mejetta S, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature. 2017;541(7635):41-45.
17.Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis. 2016;5:e189.
18.Zhang T, Zhao Q, Xiao XR, et al. Modulation of lipid metabolism by celastrol. J Proteome Res. 2019;18(3):1133-1144.
19.Zhang Y, Geng C, Liu X, et al. Celastrol ameliorates liver metabolic damage caused by a high-fat diet through Sirt1. Mol Metab. 2017;6(1):138-147.
20.Liu J, Lee J, Salazar Hernandez MA, et al. Treatment of obesity with celastrol. Cell. 2015;161(5):999-1011.
21.Feng X, Guan D, Auen T, et al. IL1R1 is required for celastrols leptin-sensitization and antiobesity effects. Nat Med. 2019;25(4):575-582.
22.Tsun ZY, Possemato R. Amino acid management in cancer. Semin Cell Dev Biol. 2015;43:22-32.
23.Bhutia YD, Babu E, Ramachandran S, et al. Amino Acid transporters in cancer and their relevance to "glutamine addiction": novel targets for the design of a new class of anticancer drugs. Cancer Res. 2015;75(9):1782-1788.
24.Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9(10):1269-1274.
25.Okamoto A, Nikaido T, Ochiai K, et al. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res. 2005;11(16):6030-6039.
26.Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res. 2006;12(4):1144-1151.
27.Ninomiya S, Hara T, Tsurumi H, et al. Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol. 2011;90(4):409-416.28.Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205-214.
28.Soliman H, Mediavilla-Varela M, Antonia S. Indoleamine 2,3-dioxygenase: is it an immune suppressor? Cancer J. 2010;16(4):354-359.
30.Prendergast GC, Malachowski WP, DuHadaway JB, et al. Discovery of IDO1 Inhibitors: from bench to bedside. Cancer Res. 2017;77(24):6795-6811.
31.Yunpeng Qi RW, Liang Zhao,Lei Lv,et al. Celastrol suppresses tryptophan catabolism in human colon cancer cells as revealed by metabolic profiling and targeted metabolite analysis. Biol Pharm Bull. 2018;41:1243-1250.
32.Hu Y, Chen X, Xu Y, et al. Hierarchical assembly of hyaluronan coated albumin nanoparticles for pancreatic cancer chemoimmunotherapy. Nanoscale. 2019;11(35):16476-1687.
33.Spano D, Zollo M. Tumor microenvironment: a main actor in the metastasis process. Clin Exp Metastasis. 2012;29(4):381-395.
34.Choi SY, Collins CC, Gout PW, Wang Y. Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite? J Pathol. 2013;230(4):350-355.
35.Brand A, Singer K, Koehl GE, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24(5):657-671.
36.Clevers H. At the crossroads of inflammation and cancer. Cell. 2004;118(6):671-674.
37.Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol. 2013;13(6):397-411.
38.Amores-Iniesta J, Barbera-Cremades M, Martinez CM, et al. Extracellular ATP activates the NLRP3 inflammasome and is an early danger signal of skin allograft rejection. Cell Rep. 2017;21(12):3414-3426.
39.Lee HE, Lee JY, Yang G, et al. Inhibition of NLRP3 inflammasome in tumor microenvironment leads to suppression of metastatic potential of cancer cells. Sci Rep. 2019;9(1):12277.
40.Qu D WL, Qin Y,Guo M,et al. Non-triggered sequential-release liposomes enhance anti-breast cancer efficacy of STS and celastrol-based microemulsion. Biomater Sci. 2018;6(12):3284-3299.
41.Liu Q, Chen F, Hou L, et al. Nanocarrier-mediated chemo-immunotherapy arrested cancer progression and induced tumor dormancy in desmoplastic melanoma. ACS Nano. 2018;12(8):7812-7825.
42.Carbonaro M, Grant G. Absorption of quercetin and rutin in rat small intestine. Ann Nutr Metab. 2005;49(3):178-182.
43.Trinh HT, Joh EH, Kwak HY, et al. Anti-pruritic effect of baicalin and its metabolites, baicalein and oroxylin A, in mice. Acta Pharmacol Sin. 2010;31(6):718-724.
44.Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500(7464):541-546.
45.张婷,王义坤, 赵琦,等. 基于UPLC-Q-TOF-MS的雷公藤红素的代谢组学研究. 中国中药杂志. 2019;44(16):3562-3568.
46.Ganapathy A, Subramenium SS, Jonathan S. et al. Enterotoxigenic Escherichia coli heat labile enterotoxin inhibits intestinal ascorbic acid uptake via a cAMP-dependent NF-κB-mediated pathway. Am J Physiol Gastrointest Liver Physiol 2019;316(1):G55-G63.
47.胡维岳. 雷公藤红素对大鼠肥胖的治疗作用及机制研究. 南京医科大学. 2018.
文章导航

/