中国科技论文统计源期刊 中文核心期刊  
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊  
日本科学技术振兴机构数据库(JST)
第七届湖北十大名刊提名奖  
医药导报, 2017, 36(9): 1021-1023
doi: 10.3870/j.issn.1004-0781.2017.09.018
蒲公英抗肿瘤作用研究进展
谭婉燕1,, 肖蒙2,

摘要:

抗肿瘤作用是近年来国内外蒲公英药理作用研究的热点。研究显示,蒲公英具有抗乳腺癌、抗肝癌、抗胃癌及抗其他肿瘤作用,其作用机制机制主要包括调控细胞周期、破坏肿瘤细胞形态、诱导细胞凋亡、抑制肿瘤细胞的迁移和侵袭等。蒲公英作为抗肿瘤的天然中草药具有非常大的潜力。

关键词: 蒲公英 ; 抗肿瘤作用 ; 天然药物

Abstract:

蒲公英为菊科植物蒲公英、碱地蒲公英或同属数种植物的干燥全草,性苦、甘、寒,具有清热解毒、消肿散结、利尿通淋的功效[1]。蒲公英始载于《唐本草》,在中国等亚洲国家已经有几千年的应用历史,它具有保肝利胆、抗菌、抗氧化、抗炎、抗肿瘤等作用[2-4]。我国蒲公英种类多达70种,除东南及华南省区外,几乎遍及全国,西北、华北及西南省区最多,华中、华东略少,其中新疆或西北省区与中亚国家共同分布的种最多[5],具有资源丰富、价格低廉的优点。

抗肿瘤作用是近年来国内外蒲公英药理作用研究的热点,研究者通过体外和体内实验检测了不同蒲公英提取物对肿瘤的影响,并对相关机制进行了探究。

1 蒲公英抗乳腺癌作用

NIU等[6]提取了蒲公英中的多糖组分,研究了其对人乳腺癌细胞MCF-7增殖的影响。结果显示,蒲公英多糖在50,100,200和400 μg·mL-1均能显著抑制肿瘤细胞的生长,且蒲公英多糖浓度越高,作用时间越长,肿瘤细胞的活力越低。进一步检测细胞凋亡相关蛋白发现,经100,200和400 μg·mL-1蒲公英多糖处理后的肿瘤细胞明显上调抑癌基因p53和促凋亡基因bax的表达,明显下调抑制凋亡基因bcl-2的表达,说明蒲公英多糖抑制肿瘤细胞增殖的机制与细胞凋亡有关。通过皮下注射MCF-7细胞的方式构建BALB/c无胸腺小鼠的异种移植模型,结果显示,20,40和80 mg·kg-1蒲公英多糖能够显著减小实体肿瘤的体积。该研究证明蒲公英多糖在体内体外均有较好的抑制肿瘤作用。

LI等[7]使用31.25,62.5,125,250 μg·mL-1蒲公英乙醇提取物处理人乳腺癌MCF-7和MDA-MB-231细胞,24 h的半数抑制浓度(IC50)分别为161.9和131.0 μg·mL-1,说明蒲公英乙醇提取物对两种肿瘤细胞均有较好的抑制作用,尤其对MDA-MB-231细胞更加敏感。进一步研究表明,蒲公英乙醇提取物能将两种乳腺癌细胞阻滞于G2/M期,使肿瘤细胞无法进入有丝分裂期,并通过激活caspase-3途径诱导肿瘤细胞凋亡。该研究还将CHOP基因的siRNA转染入MDA-MB-231细胞内,流式细胞仪结果显示CHOP基因的siRNA能够阻滞蒲公英乙醇提取物诱导的肿瘤细胞凋亡,说明CHOP基因与该过程有关。

OH等[8]认为蒲公英具有选择性雌激素受体调节器的功能,可以作为一种激素替代疗法用于绝经后女性的乳腺癌治疗。研究者检测了pS2和PR这两种雌激素调节基因的表达,发现MCF-7细胞经不同浓度的蒲公英乙醇提取物处理后,pS2基因和PR基因的mRNA表达水平显著增加,提示了蒲公英乙醇提取物具有雌激素的活性。

史栋栋[9]分析发现蒲公英含有木犀草素、羽扇豆醇、蒲公英甾醇乙酸酯、蒲公英萜醇、咖啡酸等5种潜在活性成分。木犀草素可以将MCF-7细胞的增殖抑制在S期,羽扇豆醇可将其抑制在G1期。

PENG等[10]研究发现蒲公英能较好抑制乳腺癌细胞的增殖,其水提物和醇提物的IC50值分别为306和166 μg·mL-1

2 蒲公英抗肝癌作用

蒙旭[11]以人肝癌HepG2细胞为研究对象,研究了乙酰蒲公英萜醇对肿瘤细胞增殖、迁移、侵袭的抑制作用。结果显示,乙酰蒲公英萜醇在1.6 mg·mL-1的浓度下对HepG2细胞的抑制率高达73.19%,24 h的IC50值为0.69 mg·mL-1;细胞划痕实验显示,乙酰蒲公英萜醇对肝癌细胞迁移能力有抑制作用。MINGARRO等[12]观察到蒲公英的80%甲醇提取物IC50值为15 μg·mL-1

郭君宾等[13]研究发现蒲公英提取物能显著抑制抗凋亡蛋白(Survivin、BCL-xL和BCL- 2)的表达,促进促凋亡蛋白( Smac和caspase-3/7/9) 的表达,提示蒲公英提取物对肝癌HepG2细胞增殖的抑制作用与线粒体调控的内在途径诱发HepG2细胞凋亡的机制相关。蒙旭[11]的实验结果显示,蒲公英提取物可能通过抑制PI3K/AKT通路而促进HepG2细胞的凋亡。

YOON等[14]发现蒲公英针对肝癌细胞Huh-7可以作为一种全新的TRAIL肿瘤坏死因子相关凋亡配体致敏剂,通过抑制MKK7-TIPRL相互作用,激活MKK7/JNK途径,强化肿瘤坏死因子相关凋亡配体诱导的肿瘤细胞凋亡。REHMAN等[15]通过锥虫蓝染色发现,200 μg·mL-1蒲公英叶提取物对Huh-7细胞无明显毒性。

陈红林[16]等观察到,HepG2细胞经蒲公英提取物作用后,活细胞数减少,细胞碎片明显增加。由此推测蒲公英提取物可以促使肿瘤细胞变形甚至破裂,电解质漏出从而死亡。

3 蒲公英抗胃癌作用

郭钦钰等[17]研究显示,蒲公英可抑制胃癌BGC823细胞的迁移、侵袭。1.0 mg·mL-1蒲公英组胃癌BGC823细胞中基质金属酶基因MMP2相对量为0.82,2.5 mg·mL-1蒲公英组MMP2相对量为0.35,与对照组比较均差异有统计学意义(P<0.05),提示蒲公英可能通过调控MMP2来控制肿瘤细胞的侵袭和迁移。YAMABE等[18]得到蒲公英的4种有机溶剂(正己烷、三氯甲烷、正丁醇、乙酸乙酯)的提取物,其中乙酸乙酯部分有较好的抗肿瘤活性,在100和200 μg·mL-1对胃癌AGS细胞抑制率分别达到23.7%和19.6%。进一步研究发现,蒲公英中木犀草素对AGS细胞的增殖抑制作用最强,且体内实验表明其抗肿瘤机制是由于激活caspase-3和caspase-8。

4 蒲公英对其他肿瘤的作用

LEE等[19]使用超声提取法制备朝鲜蒲公英提取物,冻干成粉末在-4 ℃保存。MTT法检测不同浓度(0,12.5,25,50,100和200 μg·mL-1)蒲公英提取物对人黑色素瘤细胞A375P和A375SM的作用结果显示,在50~200 μg·mL-1浓度范围内,蒲公英提取物能显著降低两种肿瘤细胞的细胞活力,且该抑制细胞作用具有浓度依赖性。A375P和A375SM细胞经25,50 μg·mL-1蒲公英提取物处理后,细胞内DNA断裂,核染色质固缩,提示发生了细胞凋亡。进一步检测凋亡相关蛋白的表达,发现与对照组相比两种细胞系中p53、Bax以及断裂的PARP、caspase-9蛋白表达量均显著升高,Bcl-2蛋白的表达量则下降,说明蒲公英提取物能够诱导人黑色素瘤细胞的凋亡。进一步研究表明,蒲公英提取物能显著抑制A375P细胞中Erk1/2磷酸化水平,对A375SM细胞系则几乎无影响,提示蒲公英提取物是通过Erk1/2信号通路发挥诱导肿瘤细胞凋亡的作用。

OVADJE等[20]对蒲公英根水提物进行了体外和体内实验研究。由于提取物的组成较为复杂,他们认为蒲公英根水提物能激活多种信号通路诱导肿瘤细胞凋亡。实验结果显示,蒲公英根水提物能剂量和时间依赖性地降低人结肠癌细胞HT-29(p53敲除)和HCT116(p53野生型)细胞的活力,半数有效浓度(EC50)分别为2.0 和3.5 mg·mL-1,且对正常结肠黏膜上皮细胞NCM460无抑制作用,证实蒲公英根水提物对肿瘤细胞的选择性。蒲公英根水提物能有效促进肿瘤细胞凋亡,且这种作用与p53基因无关。蒲公英根水提物处理结肠癌HT-29细胞后能引发细胞线粒体膜电位破坏,将HT-29细胞中的线粒体分离出来经蒲公英根水提物处理,线粒体内活性氧含量显著升高,提示线粒体可能是蒲公英发挥抗肿瘤作用的靶点之一。该实验还观察到,蒲公英根水提物能选择性诱导结肠癌细胞HT-29中的Bid蛋白转移到线粒体中,活化caspase- 3从而诱导细胞凋亡。

OVADJE等[21-22]对人胰腺癌细胞BxPC-3和PANC-1,慢性骨髓单核细胞性白血病细胞MV-4-11、 HL-60和U-937进行了相似的研究,发现蒲公英根水提物能够诱导肿瘤细胞凋亡,而对正常细胞无杀伤作用,其机制主要通过破坏线粒体膜电位,引发细胞自噬等。

FELENDA等[23]对来自9种肿瘤实体的19种细胞系和正常成纤维细胞进行蒲公英体外抗肿瘤活性测试,结果显示蒲公英提取物能够浓度依赖性地抑制所测的19种细胞的增殖,平均IC50值为90 mg·mL-1,对正常成纤维细胞的IC50值为128 mg·mL-1。蒲公英提取物能够抑制肿瘤细胞的侵袭和迁移,诱导肿瘤细胞凋亡。

5 结束语

相比化学治疗,天然植物作为抗肿瘤药物,具有毒副作用小、资源丰富、降低肿瘤细胞耐药性、提高患者生活质量等优点,因此被广泛应用。研究显示,蒲公英对各类肿瘤细胞的增殖均有较强的抑制作用,但是对于不同的细胞系,其EC50、IC50值差异较大,因此在未来蒲公英的开发过程中,应该考虑蒲公英不同部位的提取物及其对不同肿瘤类型抗肿瘤作用的差异性。

蒲公英抗肿瘤的作用机制主要包括调控细胞周期、破坏肿瘤细胞形态、诱导细胞凋亡、抑制肿瘤细胞的迁移和侵袭等。目前报道关于蒲公英诱导细胞凋亡的信号通路较多,有望构建成熟的信号网络。

近年来国内外对于蒲公英抗肿瘤作用的研究以体外细胞实验居多,动物体内实验较少,因此在整体动物水平上还有待进一步的实验研究。蒲公英作为抗肿瘤的天然中草药具有非常大的潜力,未来可以尝试进行蒲公英抗肿瘤作用的体内实验,并进一步研究其抗肿瘤机制,为今后开发新的天然药物奠定基础。

The authors have declared that no competing interests exist.

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目的:研究蒲公英提取物抗人肝癌细胞HepG2增殖的作用及机制.方法:采用体外培养的人肝癌细胞HepG2为研究对象,HepG2细胞经蒲公英提取物处理后,通过MTT比色法研究蒲公英提取物抗HepG2细胞增殖的作用;通过Western Blot检测线粒体介导癌细胞凋亡相关蛋白(Survivin、Mcl-1、BCL-xL、BCL-2、Smac、BAX、Bad、Cyto-chrome c及Caspase-3/7/9)的表达,对其抗HepG2细胞增殖的机制进行研究.结果:蒲公英提取物能明显抑制HepG2细胞增殖;能显著抑制HepG2细胞中抗凋亡蛋白(Survivin、BCL-xL和BCL-2)的表达,促进促凋亡蛋白(Smac 和Caspase-3/7/9)的表达,促进Cytochrome c从线粒体释放到细胞质中.其作用呈浓度依赖性.结论:蒲公英提取物能明显抑制HepG2细胞增殖,其机制与线粒体介导的癌细胞凋亡相关.
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[14] YOON J Y,CHO H S,LEE J J,et al.Novel TRAIL sensiti-zer Taraxacum Offcinale F.H. Wigg enhances TRAIL-induced apoptosis in Huh7 cells[J].Mole Carcinog,2016,55(4):387-396.
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[15] REHMAN S,IJAZ B,FATIMA N,et al.Therapeutic poten-tial of taraxacum officinale against HCV NS5B polymerase:in-vitro and in silico study[J].Biomed Pharmacoth,2016,83:881-891.
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[16] 陈红林,乔华,孙体健.蒲公英花提取物的体外抗肿瘤活性研究[J].中国药物与临床,2014,14(9):1179-1181.
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[17] 郭钦钰,陈逸轩,杨剑,.蒲公英对胃癌BGC823细胞迁移、侵袭作用的影响[J].卫生职业教育,2015,33(9):142-144.
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[18] YAMABE N,KANG K S,LEE A Y,et al.Identification of anti-cancer active components of taraxacum coreanum on human gastric cancer AGS cells[J].J Korean Soci Appl Biolog Chem,2014,57(2):187-190.
Anti-cancer effects were compared amongst Taraxacum coreanum extract, its fractions, and 7 ingredients (β-sitosterol, daucosterol, taraxasteryl acetate, chrysoeriol, diosmetin, luteolin, and luteoloside). Exposure to the ethyl acetate fraction (50 and 100 μg/mL) of T. coreanum extract and luteolin (10 and 50 μM) for 24 h induced the cleavage of poly (ADP-ribose) polymerase (PARP), caspase-3, and caspase-8, in a dose-dependent manner. These findings demonstrate that luteolin is the main active component of T. coreanum extract activating caspases-3 and -8 which contribute to apoptotic cell death.
DOI:10.1007/s13765-014-4031-2      URL    
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[19] LEE H M,SHIN S A,CHOO G S,et al.Anticancer effects of Ixeris dentata(Thunb.ex Thunb.) nakai extract on human melanoma cells A375P and A375SM[J].J Ethnopharm,2016,38(194):1022-1031.
Abstract ETHNOPHARMACOLOGICAL RELEVANCE: The plant species Taraxacum coreanum (TC), Youngia sonchifolia (YS), and Ixeris dentata (ID) belong to the family Compositae and are used for medicinal purposes in traditional medicine. However, the anticancer effects of TC, YS, and ID extracts and the underlying molecular mechanisms in melanoma cells have not been elucidated. AIM OF THE STUDY: To investigate the potential anticancer effects of TC, YS, and ID extracts on human melanoma cells and explore the potential pharmacological mechanisms in vitro and in vivo. MATERIALS AND METHODS: In this comparative study, we investigated the effects of TC, YS, and ID extracts on cell proliferation in human melanoma A375P and A375SM cells using MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays. Apoptotic cells were detected by 4',6-diamidino-2-phenylinodole (DAPI) staining. We also investigated whether the growth-inhibitory effects were associated with the induction of apoptosis and whether the mechanisms of cell death were the result of signaling molecules such as p53, Bax, Bcl-2, caspase-9, Poly-ADP ribose polymerase (PARP), and Erk (Extracellular signal-regulated protein kinase) 1/2. The in vivo antitumor effects were evaluated by measuring the tumor volume and weight and performing Terminal deoxynucleotidyl transferase (TdT) dUTP Nick End Labeling (TUNEL) assay and immunohistochemistry (IHC) in tumor xenograft models. RESULTS: TC, YS, and ID extracts effectively inhibited the growth of A375P and A375SM cells. In addition, several apoptotic events were observed following treatment, including DNA fragmentation and chromatin condensation by DAPI staining. The extracts increased p53, Bax, cleaved-caspase-9 and cleaved-PARP expression, whereas the expression of Bcl-2 was decreased in both cell lines. Furthermore, ID extract significantly inhibited the activation of Erk1/2 in both cell lines. Among the three extracts, ID had the strongest apoptotic effects. The administration of ID extract to mice inhibited tumor growth without any toxicity following 4 weeks of treatment. This extract increased the expression of apoptotic cells and p53 protein and decreased phospho-Erk1/2 protein. CONCLUSION: TC, YS, and ID extracts suppress the growth of human melanoma cells through apoptosis. Among these extracts, ID has the strongest anticancer and apoptotic effects. It induces apoptosis through the inhibition of Erk1/2 in A375P and A375SM human melanoma cells and in tumor xenograft models and may be a potential chemotherapeutic agent against melanoma. Copyright 漏 2016 Elsevier Ireland Ltd. All rights reserved.
DOI:10.1016/j.jep.2016.11.010      PMID:27836777      URL    
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[20] OVADJE P,AMMAR S,GUERRERO J A,et al.Dandelion root extract affects colorectal cancer proliferation and survival through the activation of multiple death signalling pathways[J].Oncotarget,2016,7(45):73080-73100.
Abstract Dandelion extracts have been studied extensively in recent years for its anti-depressant and anti-inflammatory activity. Recent work from our lab, with in-vitro systems, shows the anti-cancer potential of an aqueous dandelion root extract (DRE) in several cancer cell models, with no toxicity to non-cancer cells. In this study, we examined the cancer cell-killing effectiveness of an aqueous DRE in colon cancer cell models. Aqueous DRE induced programmed cell death (PCD) selectively in > 95% of colon cancer cells, irrespective of their p53 status, by 48 hours of treatment. The anti-cancer efficacy of this extract was confirmed in in-vivo studies, as the oral administration of DRE retarded the growth of human colon xenograft models by more than 90%. We found the activation of multiple death pathways in cancer cells by DRE treatment, as revealed by gene expression analyses showing the expression of genes implicated in programmed cell death. Phytochemical analyses of the extract showed complex multi-component composition of the DRE, including some known bioactive phytochemicals such as 伪-amyrin, 尾-amyrin, lupeol and taraxasterol. This suggested that this natural extract could engage and effectively target multiple vulnerabilities of cancer cells. Therefore, DRE could be a non-toxic and effective anti-cancer alternative, instrumental for reducing the occurrence of cancer cells drug-resistance.
DOI:10.18632/oncotarget.11485      PMID:27564258      URL    
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[21] OVADJE P,CHOCHKEH M,AKBARI-ASL P,et al.Selective induction of apoptosis and autophagy through treatment with dandelion root extract in human pancreatic cancer cells[J].Pancreas,2012,41(7):1039-1047.
Pancreatic cancer has a 100% mortality rate; the aim of this study is to evaluate the efficacy of dandelion root extract (DRE) in inducing apoptosis and autophagy in aggressive and resistant pancreatic cancer cells.The effect of DRE was evaluated using WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate) assay. Apoptotic cell death was confirmed by nuclear condensation by Hoechst staining and externalization of phosphatidylserine to the outer leaflet of the plasma membrane by Annexin-V binding assay. Loss of mitochondrial membrane potential was observed using the JC-1 (5,5',6, 6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolylcarbocyanine iodide) dye. The induction of autophagy was detected using a monodansylcadaverine assay and this was confirmed by immunofluorescence for light chain 3-II.BxPC-3 and PANC-1 pancreatic cells were sensitive to aqueous DRE. This extract induces selective apoptosis in a dose- and time-dependent manner. Dandelion root extract caused the collapse of the mitochondrial membrane potential, leading to prodeath autophagy. Normal human fibroblasts were resistant at similar doses.We demonstrate that DRE has the potential to induce apoptosis and autophagy in human pancreatic cancer cells with no significant effect on noncancerous cells. This will provide a basis on which further research in cancer treatment through DRE can be executed.
DOI:10.1097/MPA.0b013e31824b22a2      PMID:22647733      URL    
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[22] OVADJE P,HAMM C,PANDEY S.Efficient induction of extrinsic cell death by dandelion root eExtract in human chronic myelomonocytic leukemia(CMML) cells[J].PLos One,2012,7(2):e30601-e30604.
Background Chronic Myelomonocytic Leukemia (CMML) is a heterogeneous disease that is not only hard to diagnose and classify, but is also highly resistant to treatment. Available forms of therapy for this disease have not shown significant effects and patients rapidly develop resistance early on in therapy. These factors lead to the very poor prognosis observed with CMML patients, with median survival duration between 12 and 24 months after diagnosis. This study is therefore centered around evaluating the selective efficacy of a natural extract from dandelion roots, in inducing programmed cell death in aggressive and resistant CMML cell lines. Methodology/Principal Findings To confirm the induction of programmed cell death in three human CMML cell lines, nuclear condensation and externalization of the phosphatidylserine, two main characteristics of apoptosis, were detected using Hoechst staining and annexin-V binding assay. The induction of another mode of cell death, autophagy, was determined using a monodansylcadaverine (MDC) stain, to detect the formation of autophagy vacuoles. The results from this study indicate that Dandelion Root Extract (DRE) is able to efficiently and selectively induce apoptosis and autophagy in these cell lines in a dose and time dependent manner, with no significant toxicity on non-cancerous peripheral blood mononuclear cells. More importantly, we observed early activation of initiator caspase-8, which led to mitochondrial destabilization and the induction of autophagy, suggesting that DRE acts through the extrinsic pathway of apoptosis. The inability of DRE to induce apoptosis in dominant-negative FADD cells, confirms the mechanism of action of DRE in in vitro models of CMML. Conclusion The results from this study indicate that natural products, in particular Dandelion Root Extract, have great potential, as non-toxic and effective alternatives to conventional modes of chemotherapy available today.
DOI:10.1371/journal.pone.0030604      PMID:22363452      URL    
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[23] FELENDA J,BECKMANN C,STINTZING F C.Investigation of the impact of Viscum album preparations on the proliferation of the equine sarcoid cell line E42/02[J].Phytomedicine,2015,22(Suppl):S25.
DOI:10.1016/j.phymed.2015.05.065      URL    
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关键词(key words)
蒲公英
抗肿瘤作用
天然药物


作者
谭婉燕
肖蒙