Please wait a minute...
浙江大学学报（医学版）
浙江大学学报（医学版）  2016, Vol. 45 Issue (5): 501-507    DOI: 10.3785/j.issn.1008-9292.2016.09.08
中药分子药理专题     
双氢青蒿素抗肿瘤分子生物学机制研究进展
曹鹏, 冷东瑾, 李滢, 张紫薇, 刘磊, 李晓岩
东北林业大学生命科学学院, 黑龙江 哈尔滨 150040
Progress on anti-tumor molecular mechanisms of dihydroartemisinin
CAO Peng, LENG Dongjin, LI Ying, ZHANG Ziwei, LIU Lei, LI Xiaoyan
College of Life Science, Northeast Forest University, Harbin 150040, China
 全文: PDF(762 KB)   HTML ( ) 
摘要：

青蒿素作为抗疟特效药在临床应用中存在水溶性小、口服效果差等缺点，因此研究人员开发了保留其母核的多种衍生物。其中双氢青蒿素（DHA）的抗疟活性更强，且具有在体内代谢速度快、水溶性好等优点，同时DHA对肿瘤细胞也有良好的抑制效果，且其分子生物学作用机制与自身结构中的过氧桥密切相关。由于肿瘤细胞比正常细胞需要摄取更多的铁离子，因此肿瘤细胞膜上存在大量的转铁蛋白受体。DHA能在亚铁离子的存在下使过氧桥发生断裂，产生自由基从而对肿瘤细胞发挥杀伤作用，并能使转铁蛋白受体发生内吞，阻止肿瘤细胞从外界摄入必需的铁离子。本文主要从DHA加速细胞氧化损伤、诱导肿瘤细胞凋亡、抑制肿瘤细胞生长增殖和侵袭转移以及逆转肿瘤细胞多药耐药等方面对其抗肿瘤的分子生物学机制进行综述。
关键词： 青蒿素/类似物和衍生物;  青蒿素/药理学;  抗肿瘤药(中药)/治疗应用;  细胞凋亡/药物作用;  细胞增殖/药物作用;  肿瘤侵润;  肿瘤转移;  综述    
Abstract:

Artemisinin is an anti-malarial drug with poor water solubility and oral absorption; so a variety of derivatives based on the parent nucleus have been developed. Compared with artemisinin, dihydroartemisinin (DHA) has a stronger anti-malaria activity, and has the advantages of high metabolic rate and better water solubility. Recent studies have discovered that DHA has a good inhibitory effect on tumor cells, which is closely related to the peroxide bridge in its molecular structure. Since tumor cells need more Fe3+ than normal cells, there are a large number of transferrin receptors on the tumor cell membrane. DHA can break the peroxide bridge in the presence of Fe2+, and the free radicals generated can play its lethal effect on tumor cells. In addition, DHA can promote endocytosis of transferrin receptor, and thus prevent cancer cells from taking Fe3+ from microenvironment. This article reviews the anti-tumor molecular mechanism of DHA, including accelerating oxidative damage, inducing apoptosis, inhibiting the growth, proliferation and invasion of tumor cells, reversing tumor multidrug resistance.
Key words: Artemisinin/analogs &    derivatives    Artemisinin/pharmacology    Antineoplastic drugs (TCD)/therapeutic use    Apoptosis/drug effects    Cell proliferation/drug effects    Neoplasm invasiveness    Neoplasm metastasis    Review
收稿日期: 2015-10-23 出版日期: 2016-09-25
CLC:  R966  
基金资助:

中央高校基本科研业务费专项资金（2572014CA23）；中国博士后科学基金（2013M541328）；东北林业大学大学生创新创业训练计划（201510225150）
通讯作者: 李晓岩(1982-),女,博士,讲师,主要从事抗癌活性物质的开发研究;E-mail:xyli821187@163.com;http://orcid.org/0000-0001-8743-7632     E-mail: xyli821187@163.com
作者简介: 曹鹏(1994-),男,硕士研究生,主要从事抗癌活性物质的相关研究;E-mail:beiguoxueyan211@139.com;http://orcid.org/0000-0001-7031-2550
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　　

引用本文:

曹鹏 等. 双氢青蒿素抗肿瘤分子生物学机制研究进展[J]. 浙江大学学报（医学版）, 2016, 45(5): 501-507.

CAO Peng, LENG Dongjin, LI Ying, ZHANG Ziwei, LIU Lei, LI Xiaoyan. Progress on anti-tumor molecular mechanisms of dihydroartemisinin. Journal of ZheJiang University(Medical Science), 2016, 45(5): 501-507.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2016.09.08    或    http://www.zjujournals.com/med/CN/Y2016/V45/I5/501

[1] SIEGEL R, NAISHADHAM D, JEMAL A.Cancer statistics, 2012[J].C A Cancer J Clin, 2012, 62(1):10-29.
[2] HOLOHAN C, VAN SCHAEYBROECK S, LONGLEY D B, et al.Cancer drug resistance:an evolving paradigm[J].Nat Rev Cancer, 2013, 13(10):714-726.
[3] BURAGOHAIN P, SAIKIA B, SURINENI N, et al.Synthesis of a novel series of artemisinin dimers with potent anticancer activity involving Sonogashira cross-coupling reaction[J].Bioorg Med Chem Lett, 2014, 24(1):237-239.
[4] KUWANO K.Involvement of epithelial cell apoptosis in interstitial lung diseases[J].Intern Med, 2008, 47(5):345-353.
[5] CARO J T, MARÍN L M, IAZBIK M C, et al.Markers of iron metabolism in retired racing greyhounds with and without osteosarcoma[J].Vet Clin Pathol, 2013, 42(3):360-363.
[6] ONTIKATZE T, RUDNER J, HANDRICK R, et al.Dihydroartemisinin is a hypoxia-active anti-cancer drug in colorectal carcinoma cells[J].Front Oncol, 2014, 4:116.
[7] LU Y Y, CHEN T S, WANG X P, et al.Single-cell analysis of dihydroartemisinin-induced apoptosis through reactive oxygen species-mediated caspase-8 activation and mitochondrial pathway in ASTC-a-1 cells using fluorescence imaging techniques[J].J Biomed Opt, 2010, 15(4):046028.
[8] BA Q, ZHOU N, DUAN J, et al.Dihydroartemisinin exerts its anticancer activity through depleting cellular iron via transferrin receptor-1[J/OL].PLoS One, 2012, 7(8):e42703.
[9] ASIF M, IQBAL M A, HUSSEIN M A, et al.Human colon cancer targeted pro-apoptotic, anti-metastatic and cytostatic effects of binuclear Silver (I) eN-Heterocyclic carbene (NHC) complexes[J].Eur J Med Chem, 2015, 108:177-187.
[10] LU J J, CHEN S M, ZHANG X W, et al.The anti-cancer activity of dihydroartemisinin is associated with induction of iron-dependent endoplasmic reticulum stress in colorectal carcinoma HCT116 cells[J].Invest New Drugs, 2011, 29(6):1276-1283.
[11] LU M, SUN L, ZHOU J, et al.Dihydroartemisinin-induced apoptosis is associated with inhibition of sarco/endoplasmic reticulum calcium ATPase activity in colorectal cancer[J].Cell Biochem Biophys, 2015, 73(9):137-145.
[12] GAO X, LUO Z, XIANG T, et al.Dihydroartemisinin induces endoplasmic reticulum stress-mediated apoptosis in HepG2 human hepatoma cells[J].Tumori, 2011, 97(6):771-780.
[13] CHEN M, CHEN T S, LU Y Y, et al.Dihydroarteminsin-induced apoptosis is not dependent on the translocation of Bim to the endoplasmic reticulum in human lung adenocarcinoma cells[J].Pathol Oncol Res, 2012, 18(4):809-816.
[14] DU X X, LI Y J, WU C L, et al.Initiation of apoptosis, cell cycle arrest and autophagy of esophageal cancer cells by dihydroartemisinin[J].Biomed Pharmacother, 2013, 67(5):417-424.
[15] CHEN S S, HU W, WANG Z, et al.p8 attenuates the apoptosis indueced by dihydroartemisinin in cancer cells through promoting autophagy[J].Cancer Biol Ther, 2015, 16(5):770-779.
[16] JIA G, KONG R, MA Z B, et al.The activation of c-Jun NH2-terminal kinase is required for dihydroartemisinin-induced autophagy in pancreatic cancer cells[J].J Exp Clin Cancer Res, 2014, 33:8.
[17] AUNG W, SOGAWA C, FURUKAWA T, et al.Anticancer effect of dihydroartemisinin (D) HAin a pancreatic tumor model evaluated by conventional methods and optical imaging[J].Anticancer Res, 2011, 31(5):1549-1558.
[18] LU M, SUN L, ZHOU J, et al.Dihydroartemisinin induces apoptosis in colorectal cancer cells through the mitochondria-dependent pathway[J].Tumor Biol, 2014, 35(6):5307-5314.
[19] CABELLO C M, LAMORE S D, BAIR W B 3RD, et al.The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis[J].Invest New Drug, 2012, 30(4):1289-1301.
[20] JI Y, ZHANG Y C, PEI L B, et al.Anti-tumor effects of dihydroartemisinin on human osteosarcoma[J].Mol Cell Biochem, 2011, 351(1-2):99-108.
[21] LI Y J, ZHOU J H, DU X X, et al.Dihydroartemisinin accentuates the anti-tumor effects of photodynamic therapy via inactivation of NF-κB in Eca109 and Ec9706 esophageal cancer cells[J].Cell Physiol Biochem, 2014, 33(5):1527-1536.
[22] AN F F, LIU Y C, ZHANG W W, et al.Dihydroartemisinine enhances dictamnine-induced apoptosis via a caspase dependent pathway in human lung adenocarcinoma A549 cells[J].Asian Pac J Cancer PREV, 2013, 14(10):5895-5900.
[23] HE Q, SHI J, SHEN X L, et al.Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cells[J].Cancer Biol Ther, 2010, 9(10):819-824.
[24] KONG R, JIA G, CHENG Z X, et al.Dihydroartemisinin enhances Apo2L/TRAIL-mediated apoptosis in pancreatic cancer cells via ROS-mediated up-regulation of death receptor 5[J/OL].PLoS One, 2012, 7(5):e37222.
[25] WANG S J, GAO Y, CHEN H, et al.Dihydroartemisinin inactivates NF-kappaB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both in vitro and in vivo[J].Cancer Lett, 2010, 293(1):99-108.
[26] MAGENTA D, SANGIOVANNI E, BASILICO N, et al.Inhibition of metalloproteinase-9 secretion and gene expression by artemisinin derivatives[J].Acta Trop, 2014, 140:77-83.
[27] FENG X, LI L, JIANG H, et al.Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells:involvement of apoptosis and autophagy[J].Biochem Biophys Res Commun, 2014, 444(3):376-381.
[28] ODAKA Y, XU B, LUO Y, et al.Dihydroartemisinin inhibits the mammalian target of rapamycin-mediated signaling pathways in tumor cells[J].Carcinogenesis, 2014, 35(1):192-200.
[29] LIU Y, WANG W, XU J, et al.Dihydroartemisinin inhibits tumor growth of human osteosarcoma cells by suppressing Wnt/β-catenin signaling[J].Oncol Rep, 2013, 30(4):1723-1730.
[30] MI Y J, GENG G J, ZOU Z Z, et al.Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells[J/OL].PloS One, 2015, 10(3):e0120426.
[31] ZHANG S, MA Y, JIANG J, et al.Inhibition of urokinase-type plasminogen activator expression by dihydroartemisinin in breast cancer cells[J].Oncol Lett, 2014, 7(5):1375-1380.
[32] HWANG Y P, YUN H J, KIM H G, et al.Suppression of PMA-induced tumor cell invasion by dihydroartemisinin via inhibition of PKC a/Raf/MAPKs and NF-kappaB/AP-1-dependent mechanisms[J].Biochem Pharmacol, 2010, 79(12):1714-1726.
[33] HU C J, ZHOU L, CAI Y.Dihydroartemisinin induces apoptosis of cervical cancer cells via upregulation of RKIP and downregulation of bcl-2[J].Cancer Biol Ther, 2014, 15(3):279-288.
[34] WU B, HU K, LI S, et al.Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer[J].Oncol Rep, 2012, 27(1):101-108.
[35] D'ALESSANDRO S, BASILICO N, CORBETT Y, et al.Hypoxia modulates the effect of dihydroartemisinin on endothelial cells[J].Biochem Pharmacol, 2011, 82(5):476-484.
[36] WANG S J, SUN B, CHENG Z X, et al.Dihydroartemisinin inhibits angiogenesis in pancreatic cancer by targeting the NF-κB pathway[J].Cancer Chemoth Pharmacol, 2011, 68(6):1421-1430.
[37] HOOFT VAN HUIJSDUIJNEN R, GUY R K, CHIBALE K, et al.Anticancer properties of distinct antimalarial drug classes[J/OL].PLoS One, 2013, 8(12):e82962.
[38] ZHAO C, GAO W, CHEN T.Synergistic induction of apoptosis in A549 cells by dihydroartemisinin and gemcitabine[J/OL].Apoptosis, 2014, 19(4):668-681.
[39] CHEN T, CHEN M, CHEN J.Ionizing radiation potentiates dihydroartemisinin-induced apoptosis of A549 Cells via a caspase-8-dependent pathway[J/OL].PLoS One, 2013, 8(3):e59827.
[40] LIU Y, LIU Z, SHI J, et al.Synthesis and cytotoxicity of novel 10-substituted dihydroartemisinin derivatives containing N-arylphenyl-ethenesulfonamide groups[J].Molecules, 2013, 18(3):2864-2877.
[41] DAI L, WANG Y L, DENG L H, et al.Novel multiarm polyethylene glycol-dihydroartemisinin conjugates enhancing therapeutic efficacy in non-small-cell lung cancer[J].Sci Rep, 2014, 4:5871.
[42] RIGHESCHI C, CORONNELLO M, MASTRANTONI A, et al.Strategy to provide a useful solution to effective delivery of dihydroartemisinin:development, characterization and in vitro studies of liposomal formulations[J].Colloids Surf B Biointerfaces, 2014, 116:121-127.
[43] LIU L, WEI Y, ZHAI S, et al.Dihydroartemisinin and transferrin dual-dressed nano-graphene oxide for a pH-triggered chemotherapy[J].Biomaterials, 2015, 62:35-46.
[1] 冯梦宇,张太平,赵玉沛. 加速康复外科在胰腺外科中的应用[J]. 浙江大学学报（医学版）, 2017, 46(6): 666-674.
[2] 许晶晶 等. 影像学在肿瘤精准医疗时代的机遇和挑战[J]. 浙江大学学报（医学版）, 2017, 46(5): 455-461.
[3] 潘静颖 等. PET-CT与乳腺癌分子病理分型、治疗反应及预后的相关性研究进展[J]. 浙江大学学报（医学版）, 2017, 46(5): 473-480.
[4] 张思影 等. CT和磁共振参数反应图在肿瘤精准疗效评估中的研究进展[J]. 浙江大学学报（医学版）, 2017, 46(5): 468-472.
[5] 潘瑶 等. 胰腺癌的影像学精准诊断与评估[J]. 浙江大学学报（医学版）, 2017, 46(5): 462-467.
[6] 卞巍 等. CT在诊断卵巢转移性肿瘤病理类型和转移灶来源中的应用价值[J]. 浙江大学学报（医学版）, 2017, 46(5): 546-551.
[7] 王梦嫣 等. 耶氏肺孢子菌对磺胺类药物耐药相关基因突变的研究进展[J]. 浙江大学学报（医学版）, 2017, 46(5): 563-569.
[8] 姜贻乾 等. 微小RNA-29b对乳腺癌细胞增殖和迁移的影响及其分子生物学机制[J]. 浙江大学学报（医学版）, 2017, 46(4): 349-356.
[9] 李艳蝶 等. NLRP3炎症小体与儿童自身炎症性疾病研究进展[J]. 浙江大学学报（医学版）, 2017, 46(4): 449-453.
[10] 王丽雅 等. 借助辅助生殖技术出生子代的安全性研究进展[J]. 浙江大学学报（医学版）, 2017, 46(3): 279-284.
[11] 严恺 等. 出生缺陷相关遗传病产前诊断技术新进展[J]. 浙江大学学报（医学版）, 2017, 46(3): 227-232.
[12] 唐敏悦 等. 半乳糖凝集素1在母胎界面参与胚胎着床和妊娠维持的研究进展[J]. 浙江大学学报（医学版）, 2017, 46(3): 321-327.
[13] 傅晓华 等. 棕色脂肪组织及其与多囊卵巢综合征关系的研究进展[J]. 浙江大学学报（医学版）, 2017, 46(3): 315-320.
[14] 傅燕玲 等. 肽类激素Kisspeptin在生殖内分泌领域的应用前景[J]. 浙江大学学报（医学版）, 2017, 46(3): 328-333.
[15] 钱叶青 等. 高通量测序技术在临床遗传学中的应用[J]. 浙江大学学报（医学版）, 2017, 46(3): 334-337.