Please wait a minute...
浙江大学学报(医学版)  2021, Vol. 50 Issue (5): 601-606    DOI: 10.3724/zdxbyxb-2021-0198
专题报道     
天然药物成分干预铁死亡抑制肿瘤的作用研究进展
宣自学,张轶雯,潘宗富,郑小卫,黄萍
浙江省人民医院 杭州医学院附属人民医院临床药学研究中心药学部,浙江 杭州 310014
Natural medicinal ingredients induce tumor ferroptosis and related mechanisms
XUAN Zixue,ZHANG Yiwen,PAN Zongfu,ZHENG Xiaowei,HUANG Ping
Department of Pharmacy, Clinical Pharmacy Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
 全文: PDF(2448 KB)   HTML( 13 )
摘要:

铁死亡是一种铁依赖的程序性死亡,不同于传统的细胞死亡方式(如凋亡、焦亡、坏死、自噬),其特征是活性氧诱导脂质过氧化物堆积。铁死亡在肿瘤发生发展中发挥着重要的调控作用。最新研究表明,天然药物成分可通过谷胱甘肽/谷胱甘肽过氧化物酶4途径、铁代谢、脂质代谢等调控机制诱导肿瘤细胞铁死亡。研究发现了30多种天然药物成分具有诱导肿瘤细胞铁死亡的作用,且有多通路、多靶点的特点。本文综述了天然药物成分通过干预铁死亡抑制肿瘤的作用研究进展。

关键词: 铁死亡肿瘤天然药物中药调控机制综述    
Abstract:

Ferroptosis is an iron-dependent programmed cell death characterized by reactive oxygen species-induced lipid peroxide accumulation, which is different from cell apoptosis, pyroptosis, necrosis or autophagy. Ferroptosis plays an important role in the regulation of tumorigenesis and tumor development. Recent studies have shown that natural medicinal ingredients can induce ferroptosis in tumor cells through glutathione (GSH)/glutathione peroxidase 4 (GPx4) pathway, iron metabolism, lipid metabolism or other mechanisms. It has been reported that more than 30 natural medicinal ingredients can induce ferroptosis in tumor cells with multiple pathways and multiple targets. This article reviews the current research progress on the antitumor effects of natural medicinal ingredients through inducing cell ferroptosis.

Key words: Ferroptosis    Tumor    Natural medicine    Traditional Chinese medicine    Regulatory mechanism    Review
收稿日期: 2021-07-13 出版日期: 2021-12-29
:  R932  
基金资助: 浙江省中医药科技计划(2018ZZ006,2021ZA006)
服务  
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章  
宣自学
张轶雯
潘宗富
郑小卫
黄萍

引用本文:

宣自学,张轶雯,潘宗富,郑小卫,黄萍. 天然药物成分干预铁死亡抑制肿瘤的作用研究进展[J]. 浙江大学学报(医学版), 2021, 50(5): 601-606.

XUAN Zixue,ZHANG Yiwen,PAN Zongfu,ZHENG Xiaowei,HUANG Ping. Natural medicinal ingredients induce tumor ferroptosis and related mechanisms. J Zhejiang Univ (Med Sci), 2021, 50(5): 601-606.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0198        https://www.zjujournals.com/med/CN/Y2021/V50/I5/601

图 1  铁死亡的调控机制①SLC7A11、SLC3A2可在向细胞内转运胱氨酸的同时外排等量的谷氨酸. 胱氨酸通过还原反应可生成GSH生物合成的限速底物半胱氨酸,GSH是GPx4的辅酶因子以及其降解脂质过氧化物的必需反应底物. GPx4作为调控铁死亡的关键酶,可通过催化脂质过氧化物的还原反应,抑制铁死亡的发生. 硫转移途径、甲羟戊酸途径、谷氨酰胺途径、p53调控轴等也参与铁死亡的GSH/GPx4途径. ②血液循环中的三价铁离子与转铁蛋白结合并运输,通过细胞膜上的转铁蛋白受体1进入细胞内被还原为二价铁离子后,再被转运并释放到细胞质铁池中,导致铁过量,产生活性氧,引发铁死亡. 铁蛋白代谢相关的ATG5-ATG7-NCOA4通路和p62-Keap1-NRF2通路也可参与铁死亡过程. ③ACSL4通过在内质网相关的氧合作用中心产生氧化的PE来促进铁死亡,而ACSL4催化花生四烯酸或肾上腺素的附着以产生酰基辅酶A衍生物,随后通过LPCAT3将其酯化为PE,进而被脂氧合酶氧化以产生脂质氢过氧化物,最终导致铁死亡. SLC7A11:溶质载体家族7成员11;SLC3A2:溶质载体家族3成员2;GSH:谷胱甘肽;GPx:谷胱甘肽过氧化物酶;ATG:自噬相关基因;NCOA:核受体辅激活因子;Keap:Kelch样环氧氯丙烷相关蛋白;NRF:核因子E2相关因子;ACSL:长链脂酰辅酶A合成酶;PE:磷脂酰乙醇胺;LPCAT:溶血卵磷脂酰基转移酶;PUFA:多不饱和脂肪酸.
1 DIXONS J, LEMBERGK M, LAMPRECHTM R, et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]Cell, 2012, 149( 5): 1060-1072.
doi: 10.1016/j.cell.2012.03.042
2 STOCKWELLB R, FRIEDMANN ANGELIJ P, BAYIRH, et al.Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease[J]Cell, 2017, 171( 2): 273-285.
doi: 10.1016/j.cell.2017.09.021
3 MOUY, WANGJ, WUJ, et al.Ferroptosis, a new form of cell death: opportunities and challenges in cancer[J]J Hematol Oncol, 2019, 12( 1): 34.
doi: 10.1186/s13045-019-0720-y
4 XIAX, FANX, ZHAOM, et al.The relationship between ferroptosis and tumors: a novel landscape for therapeutic approach[J]Curr Gene Ther, 2019, 19( 2): 117-124.
doi: 10.2174/1566523219666190628152137
5 URSINIF, MAIORINOM. Lipid peroxidation and ferroptosis: the role of GSH and GPx4[J]Free Radic Biol Med, 2020, 175-185.
doi: 10.1016/j.freeradbiomed.2020.02.027
6 WANGM, LIS, WANGY, et al.Gambogenic acid induces ferroptosis in melanoma cells undergoing epithelial-to-mesenchymal transition[J]Toxicol Appl Pharmacol, 2020, 115110.
doi: 10.1016/j.taap.2020.115110
7 GAOZ, DENGG, LIY, et al.Actinidia chinensis planch prevents proliferation and migration of gastric cancer associated with apoptosis, ferroptosis activation and mesenchymal phenotype suppression[J]Biomed Pharmacother, 2020, 110092.
doi: 10.1016/j.biopha.2020.110092
8 HUANGS, CAOB, ZHANGJ, et al.Induction of ferroptosis in human nasopharyngeal cancer cells by cucurbitacin B: molecular mechanism and therapeutic potential[J]Cell Death Dis, 2021, 12( 3): 237.
doi: 10.1038/s41419-021-03516-y
9 LINY S, SHENY C, WUC Y, et al.Danshen improves survival of patients with breast cancer and dihydroisotanshinone Ⅰ induces ferroptosis and apoptosis of breast cancer cells[J]Front Pharmacol, 2019, 1226.
doi: 10.3389/fphar.2019.01226
10 LOUJ S, ZHAOL P, HUANGZ H, et al.Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer[J]Phytomedicine, 2021, 153370.
doi: 10.1016/j.phymed.2020.153370
11 ROHJ L, KIME H, JANGH, et al.Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis[J]Redox Biol, 2017, 254-262.
doi: 10.1016/j.redox.2016.12.010
12 CHENG Q, BENTHANIF A, WUJ, et al.Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis[J]Cell Death Differ, 2020, 27( 1): 242-254.
doi: 10.1038/s41418-019-0352-3
13 CHENP, LIX, ZHANGR, et al.Combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transformation[J]Theranostics, 2020, 10( 11): 5107-5119.
doi: 10.7150/thno.44705
14 ZHANGL, LIUW, LIUF, et al.IMCA induces ferroptosis mediated by SLC7A11 through the AMPK/mTOR pathway in colorectal cancer[J]Oxid Med Cell Longev, 2020, 6901472.
doi: 10.1155/2020/1675613
15 DINGY, CHENX, LIUC, et al.Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells[J]J Hematol Oncol, 2021, 14( 1): 19.
doi: 10.1186/s13045-020-01016-8
16 LINH, CHENX, ZHANGC, et al.EF24 induces ferroptosis in osteosarcoma cells through HMOX1[J]Biomed Pharmacother, 2021, 111202.
doi: 10.1016/j.biopha.2020.111202
17 CHENT C, CHUANGJ Y, KOC Y, et al.AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-mediated redox homeostasis[J]Redox Biol, 2020, 101413.
doi: 10.1016/j.redox.2019.101413
18 NIKOLOVAB, SEMKOVAS, TSONEVAI, et al.Redox-related molecular mechanism of sensitizing colon cancer cells to camptothecin analog SN38[J]Anticancer Res, 2020, 40( 9): 5159-5170.
doi: 10.21873/anticanres.14519
19 OOKOE, SAEEDM E M, KADIOGLUO, et al.Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells[J]Phytomedicine, 2015, 22( 11): 1045-1054.
doi: 10.1016/j.phymed.2015.08.002
20 DUJ, WANGT, LIY, et al.DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin[J]Free Radical Biol Med, 2019, 356-369.
doi: 10.1016/j.freeradbiomed.2018.12.011
21 ZHUH Y, HUANGZ X, CHENG Q, et al.Typhaneoside prevents acute myeloid leukemia (AML) through suppressing proliferation and inducing ferroptosis associated with autophagy[J]Biochem Biophysl Res Commun, 2019, 516( 4): 1265-1271.
doi: 10.1016/j.bbrc.2019.06.070
22 NIUY, ZHANGJ, TONGY, et al.Physcion 8-O-β-glucopyranoside induced ferroptosis via regulating miR-103a-3p/GLS2 axis in gastric cancer[J]Life Sci, 2019, 116893.
doi: 10.1016/j.lfs.2019.116893
23 TSAIY, XIAC, SUNZ. The inhibitory effect of 6-gingerol on ubiquitin-specific peptidase 14 enhances autophagy-dependent ferroptosis and anti-tumor in vivo and in vitro[J]Front Pharmacol, 2020, 598555.
doi: 10.3389/fphar.2020.598555
24 MAIT T, HAMA?A, HIENZSCHA, et al.Salinomycin kills cancer stem cells by sequestering iron in lysosomes[J]Nat Chem, 2017, 9( 10): 1025-1033.
doi: 10.1038/nchem.2778
25 KAGANV E, MAOG, QUF, et al.Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis[J]Nat Chem Biol, 2017, 13( 1): 81-90.
doi: 10.1038/nchembio.2238
26 DIXONS J, WINTERG E, MUSAVIL S, et al.Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death[J]ACS Chem Biol, 2015, 10( 7): 1604-1609.
doi: 10.1021/acschembio.5b00245
27 XIAOFEIJ, MINGQINGS, MIAOS, et al.Oleanolic acid inhibits cervical cancer HeLa cell proliferation through modulation of the ACSL4 ferroptosis signaling pathway[J]Biochem Biophysl Res Commun, 2021, 81-88.
doi: 10.1016/j.bbrc.2021.01.028
28 XIEY, ZHOUX, LIJ, et al.Identification of a new natural biflavonoids against breast cancer cells induced ferroptosis via the mitochondrial pathway[J]Bioorg Chem, 2021, 104744.
doi: 10.1016/j.bioorg.2021.104744
29 MALFAG A, TOMASELLOB, ACQUAVIVAR, et al.Betula etnensis Raf. (betulaceae) extract induced HO-1 expression and ferroptosis cell death in human colon cancer cells[J]Int J Mol Sci, 2019, 20( 11): 2723.
doi: 10.3390/ijms20112723
30 DUJ, WANGL, HUANGX, et al.Shuganning injection, a traditional Chinese patent medicine, induces ferroptosis and suppresses tumor growth in triple-negative breast cancer cells[J]Phytomedicine, 2021, 153551.
doi: 10.1016/j.phymed.2021.153551
31 WANGN, ZENGG Z, YINJ L, et al.Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in burkitt’s lymphoma[J]Biochem Biophysl Res Commun, 2019, 519( 3): 533-539.
doi: 10.1016/j.bbrc.2019.09.023
32 MBAVENGA T, FOTSOG W, NGNINTEDOD, et al.Cytotoxicity of epunctanone and four other phytochemicals isolated from the medicinal plants garcinia epunctata and ptycholobium contortum towards multi-factorial drug resistant cancer cells[J]Phytomedicine, 2018, 112-119.
doi: 10.1016/j.phymed.2017.12.016
33 MBAVENGA T, NDONTSAB L, KUETEV, et al.A naturally occuring triterpene saponin ardisiacrispin B displayed cytotoxic effects in multi-factorial drug resistant cancer cells via ferroptotic and apoptotic cell death[J]Phytomedicine, 2018, 78-85.
doi: 10.1016/j.phymed.2018.03.035
34 田颖颖,杨爱琳,陈孝男,等. 槐耳清膏抑制人非小细胞肺癌NCI-H1299细胞生长和转移及其作用机制研究[J]. 中国中药杂志, 2020, 45(15): 3700-3706
TIAN Yingying, YANG Ailin, CHEN Xiaonan, et al. Effect of Huaier aqueous extract on growth and metastasis of human non-small cell lung cancer NCI-H1299 cells and its underlying mechanisms[J]. China Journal of Chinese Materia Medica, 2020, 45(15): 3700-3706. (in Chinese)
35 SHARMAP, SHIMURAT, BANWAITJ K, et al.Andrographis-mediated chemosensitization through activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways in colorectal cancer[J]Carcinogenesis, 2020, 41( 10): 1385-1394.
doi: 10.1093/carcin/bgaa090
36 ADHAMA N, HEGAZYM E F, NAQISHBANDIA M, et al.Induction of apoptosis, autophagy and ferroptosis by thymus vulgaris and arctium lappa extract in leukemia and multiple myeloma cell lines[J]Molecules, 2020, 25( 21): 5016.
doi: 10.3390/molecules25215016
37 ADHAMA N, NAQISHBANDIA M, EFFERTHT. Cytotoxicity and apoptosis induction by fumaria officinalis extracts in leukemia and multiple myeloma cell lines[J]J Ethnopharmacol, 2021, 113458.
doi: 10.1016/j.jep.2020.113458
[1] 马丽娟,吴爽,张凯,田梅,张宏. 大麻素1型受体正电子发射断层显像在神经精神疾病中的应用进展[J]. 浙江大学学报(医学版), 2021, 50(5): 666-673.
[2] 宋飞凤,张轶雯,潘宗富,张琪,卢茜璇,黄萍. 白藜芦醇通过上调miR-186-5p表达抑制肝癌细胞迁移、侵袭和上皮-间质转化[J]. 浙江大学学报(医学版), 2021, 50(5): 582-590.
[3] 曲文政,庄英粮,李学坤. 表观遗传修饰在神经退行性变性疾病中的作用研究进展[J]. 浙江大学学报(医学版), 2021, 50(5): 642-650.
[4] 孙琦,曹蔚,罗建红. GluN3亚基的N-甲基-D-天冬氨酸受体及其在中枢神经系统的功能[J]. 浙江大学学报(医学版), 2021, 50(5): 651-658.
[5] 史建蓉,马望前,汤慧芳. 磷酸二酯酶抑制剂治疗炎性肠病的研究进展[J]. 浙江大学学报(医学版), 2021, 50(5): 659-665.
[6] 唐玥,孔元原. 遗传性酪氨酸血症Ⅰ型及其筛查和诊治进展[J]. 浙江大学学报(医学版), 2021, 50(4): 514-523.
[7] 刘飞,冯春月,毛建华,傅海东. 2019冠状病毒病疫苗接种相关新发及复发肾小球病研究进展[J]. 浙江大学学报(医学版), 2021, 50(4): 524-528.
[8] 韩连书. 新生儿遗传病基因筛查技术及相关疾病[J]. 浙江大学学报(医学版), 2021, 50(4): 429-435.
[9] 胡茫莎,韦树丽,周武源,王苹莉. 新生儿Fc受体基础研究和临床应用进展[J]. 浙江大学学报(医学版), 2021, 50(4): 537-544.
[10] 胡靖依,王青青,刘杨. 蛋白酶体亚基对肝细胞癌发生发展的调控作用研究进展[J]. 浙江大学学报(医学版), 2021, 50(3): 396-402.
[11] 葛瀛洲,刘欣梅,黄荷凤. 沉默信息调节因子家族参与病理妊娠的研究进展[J]. 浙江大学学报(医学版), 2021, 50(3): 335-344.
[12] 施锦波,励夏炜,吴育连. 基于SEER数据库分析早期胰腺导管腺癌患者能否从常用术后化疗方案中获益[J]. 浙江大学学报(医学版), 2021, 50(3): 375-382.
[13] 王锦涛,黄蕾,魏丽丽,陈炜. 重复经颅磁刺激治疗阿尔茨海默病患者的疗效影响因素[J]. 浙江大学学报(医学版), 2021, 50(3): 383-389.
[14] 庄文雯,杨咏琪,李洪亮,梁景岩. 动脉粥样硬化过程中核因子E2相关因子2对血管平滑肌细胞的调控作用[J]. 浙江大学学报(医学版), 2021, 50(3): 390-395.
[15] 朱锋,项迎春,曾玲晖. 线粒体沉默信息调节因子家族在癫痫发生发展中的作用研究进展[J]. 浙江大学学报(医学版), 2021, 50(3): 403-408.