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1.延边大学医学院肿瘤研究中心,吉林 延吉;133002
2.民族地区高发肿瘤病理生物学国家民委重点实验室(延边大学),吉林 延吉 133002
硕士研究生。研究方向:肿瘤分子生物学。E-mail:wangmengying0216@163.com
教授,博士生导师,博士。研究方向:肿瘤分子生物学。E-mail:lychen@ybu.edu.cn
纸质出版日期:2023-09-30,
收稿日期:2023-04-03,
修回日期:2023-08-15,
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王梦莹,张欣禹,杜盼等.CDDO及其衍生物抗肿瘤作用及机制的研究进展 Δ[J].中国药房,2023,34(18):2287-2292.
WANG Mengying,ZHANG Xinyu,DU Pan,et al.Research progress of anti-tumor effect and mechanism of CDDO and its derivatives[J].ZHONGGUO YAOFANG,2023,34(18):2287-2292.
王梦莹,张欣禹,杜盼等.CDDO及其衍生物抗肿瘤作用及机制的研究进展 Δ[J].中国药房,2023,34(18):2287-2292. DOI: 10.6039/j.issn.1001-0408.2023.18.21.
WANG Mengying,ZHANG Xinyu,DU Pan,et al.Research progress of anti-tumor effect and mechanism of CDDO and its derivatives[J].ZHONGGUO YAOFANG,2023,34(18):2287-2292. DOI: 10.6039/j.issn.1001-0408.2023.18.21.
2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-28-羧酸(CDDO)是以天然三萜类化合物齐墩果酸为先导物或前体,将分子中3个可修饰的官能团经过一系列化学结构改造合成的一种化合物;为了提高其抗肿瘤活性,又进一步合成了CDDO衍生物。本文归纳总结了近年来CDDO及其衍生物抗肿瘤作用及机制的研究成果,发现CDDO及其衍生物具有广泛的抗肿瘤作用,能够在微摩尔甚至纳摩尔等较低浓度下对乳腺癌、胰腺癌、肺癌和卵巢癌等表现出显著的抗肿瘤作用,其中CDDO甲酯化合物(CDDO-Me)和CDDO咪唑啉酮化合物(CDDO-Im)作用效果最为明显;CDDO及其衍生物主要通过诱导肿瘤细胞凋亡、调控代谢重编程及免疫微环境等发挥抗肿瘤活性,其涉及通路主要包括Janus蛋白酪氨酸激酶(JAK)/信号传导及转录激活蛋白3(STAT3)信号通路、核因子E2相关因子2(NRF2)信号通路、磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(又称Akt)/哺乳动物雷帕霉素靶蛋白(mTOR)信号通路、Wnt/
β
-连环蛋白(
β
-catenin)信号通路和核因子κB信号通路等。
2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid (CDDO) is a compound synthesized by taking oleanolic acid, a natural triterpene, as a precursor or precursor, and transforming three modifiable functional groups in the molecule through a series of chemical structure modification. In order to improve its anti-tumor activity, CDDO derivatives are further synthesized. In this paper, the research results of anti-tumor effects and mechanisms of CDDO and its derivatives in recent years are summarized. It is found that CDDO and its derivatives have a wide range of anti-tumor effects, and can show significant anti-tumor effects on breast cancer, pancreatic cancer, lung cancer and ovarian cancer at low concentrations such as micromole or even nanomole, among which CDDO methyl ester compound (CDDO-Me) and CDDO imidazolidinone compound (CDDO-Im) have the most obvious effects. CDDO and its derivatives exert anti-tumor activity mainly by inducing tumor cell apoptosis, and regulating metabolic reprogramming and immune microenvironment. The involved pathways mainly include Janus protein tyrosine kinase (JAK)/ signal transduction and transcription activation protein 3(STAT3) signal pathway, nuclear factor E2-related factor 2 (NRF2) signal pathway, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (also known as Akt)/mammalian rapamycin target protein (mTOR) signal pathway, Wnt/
β
-catenin signal pathway, nuclear factor κB signal pathway.
2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-28-羧酸衍生物抗肿瘤活性作用机制
derivativesanti-tumor activitymechanism of action
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季艳杰,罗浩,蔡海燕,等. CDDO-Me对三阴性乳腺癌细胞泛素特异性蛋白酶2a活性及细胞增殖的抑制作用[J]. 上海交通大学学报(医学版),2021,41(8):1025-1032.
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GAO X H,DEEB D,LIU P,et al. Role of reactive oxygen species(ROS)in CDDO-Me-mediated growth inhibition and apoptosis in colorectal cancer cells[J]. J Exp Ther Oncol,2011,9(2):119-127.
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高利昆,袁静萍,洪莉. 细胞自噬与肿瘤治疗的研究进展 [J]. 中国组织化学与细胞化学杂志,2020,29(2):183-187.
刘芳,常钰玲,宋艳梅,等. 氧化还原调节、有氧糖酵解、自噬在肿瘤中的作用及其相互关系[J]. 中国生物制品学杂志,2022,35(2):239-245,250.
WANG X Y,ZHANG X H,PENG L,et al. Bardoxolone methyl(CDDO-Me or RTA402)induces cell cycle arrest,apoptosis and autophagy via PI3K/Akt/mTOR and p38 MAPK/Erk1/2 signaling pathways in K562 cells[J]. Am J Transl Res,2017,9(10):4652-4672.
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ROGERS L J,JOHN T,PARK J,et al. Growth inhibition and apoptosis of human multiple myeloma cells induced by 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid derivatives[J]. Anticancer Drugs,2020,31(8):806-818.
TSAI T H,LIEU A S,HUANG T Y,et al. Induction of mitosis delay and apoptosis by CDDO-TFEA in gliobla-stoma multiforme[J]. Front Pharmacol,2021,12:756228.
ALABRAN J L,CHEUK A,LIBY K,et al. Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO[J]. Cancer Biol Ther,2008,7(5):709-717.
WANG Y Y,YANG Y X,ZHAO R,et al. Bardoxolone methyl induces apoptosis and autophagy and inhibits epithelial-to-mesenchymal transition and stemness in esophageal squamous cancer cells[J]. Drug Des Devel Ther,2015,9:993-1026.
CASARES L,MORENO R,ALI K X,et al. The synthetic triterpenoids CDDO-TFEA and CDDO-Me,but not CDDO,promote nuclear exclusion of BACH1 impairing its activity[J]. Redox Biol,2022,51:102291.
JANG H Y,HONG O Y,YOUN H J,et al. CDDO,a PPAR-γ ligand,inhibits TPA-induced cell migration and invasion through a PPAR-γ-independent mechanism[J]. Oncol Lett,2022,24(4):354.
SOARES I N,VIANA R,TRELFORD C B,et al. The synthetic oleanane triterpenoid CDDO-Me binds and inhibits pyruvate kinase M2[J]. Pharmacol Rep,2020,72(3):631-640.
AKUETTEH P D P,HUANG H M,WU S J,et al. Synthetic oleanane triterpenoid derivative CDDO-Me disrupts cellular bioenergetics to suppress pancreatic ductal adenocarcinoma via targeting SLC1A5[J]. J Biochem Mol Toxicol,2022,36(11):e23192.
ZHAO Y,HUO M R,XU Z H,et al. Nanoparticle deli-very of CDDO-Me remodels the tumor microenvironment and enhances vaccine therapy for melanoma[J]. Biomate-rials,2015,68:54-66.
BALL M S,BHANDARI R,TORRES G M,et al. CDDO-Me alters the tumor microenvironment in estrogen receptor negative breast cancer[J]. Sci Rep,2020,10(1):656.
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DUAN Z F,AMES R Y,RYAN M,et al. CDDO-Me,a synthetic triterpenoid,inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells[J]. Cancer Chemother Pharmacol,2009,63(4):681-689.
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罗欢,何兰,何迎春,等. 核因子-κB(NF-κB)与核因子E2相关因子2(Nrf2)信号通路交互对结直肠癌防治及中药研究的启示[J]. 中国临床药理学杂志,2021,37(10):1266-1271,1276.
KHURANA N,CHANDRA P K,KIM H,et al. Bardoxolone-methyl(CDDO-Me)suppresses androgen receptor and its splice-variant AR-V7 and enhances efficacy of enzalutamide in prostate cancer cells[J]. Antioxidants(Basel),2020,9(1):68.
MOERLAND J A,LEAL A S,LOCKWOOD B,et al. The triterpenoid CDDO-methyl ester redirects macrophage polarization and reduces lung tumor burden in a Nrf2- dependent manner[J]. Antioxidants(Basel),2023,12(1):116.
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ZHOU L,WANG Z Y,YU S B,et al. CDDO-Me elicits anti-breast cancer activity by targeting LRP6 and FZD7 receptor complex[J]. J Pharmacol Exp Ther,2020,373(1):149-159.
SHISHODIA S,SETHI G,KONOPLEVA M,et al. A synthetic triterpenoid,CDDO-Me,inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells[J]. Clin Cancer Res,2006,12(6):1828-1838.
STADHEIM T A,SUH N,GANJU N,et al. The novel tri-terpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid(CDDO)potently enhances apoptosis induced by tumor necrosis factor in human leukemia cells[J]. J Biol Chem,2002,277(19):16448-16455.
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