植物黄酮抗肿瘤效应的结构—效应关系及ROS相关作用机制研究
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摘要
植物黄酮为一类天然植物多酚化合物,广泛存在于水果、蔬菜、谷类等植物性食物中,流行病学调查和实验研究证实,植物黄酮具有抗氧化、抗炎症、抗肿瘤、抗动脉粥样硬化等广泛、优良的生物学效应,特别是对于肿瘤的发生、增殖、迁移、侵袭、血管生成以及耐药性等各阶段、各方面都具有显著的抑制作用,植物黄酮抗肿瘤活性以其天然、低毒、高效而倍受关注。
植物黄酮发挥各种药理作用的基础在于其分子结构,不同分子结构的植物黄酮其药理效应可能存在很大差异,而黄酮分子结构中某些特定的取代基或结构特征,对于植物黄酮发挥某一种特定药理效应可能是必需或极重要的,这些结构元件被称为关键结构-效应元件,研究并分析植物黄酮特定分子结构与其特定药理效应之间的构效关系,阐明其中的关键结构-效应元件,对于揭示植物黄酮特定药理学作用的机制,以及寻找高效的植物药和合成新药都具有重要的参考价值。植物黄酮抗肿瘤研究一直为国内外一个研究热点,但绝大多数研究只侧重于某一种植物黄酮的抗肿瘤效应,对不同植物黄酮化合物的抗肿瘤作用的差异研究较少,缺乏相互之间的比较,特别是对于植物黄酮特定分子结构与其抗肿瘤效应之间的构效关系缺乏研究,其中的关键结构-效应元件尚不清楚,因此值得深入探讨。
植物黄酮等多酚类化合物作为优良的天然抗氧化剂已众所周知,但事实上植物黄酮可同时具有抗氧化和促氧化两种相反特性。研究表明,在某些环境下(如O_2大量存在或细胞过氧化物酶活性较高),或某些因素诱导下(如过渡金属Fe或Cu的催化),植物黄酮可被过氧化物酶氧化生成酚自由基,并形成酚氧化反应链,这些酚过氧化物可催化谷胱甘肽或辅酶Ⅰ共氧化并产生活性氧。植物黄酮对疾病的防治作用一般认为在于其优良的抗氧化及清除自由基特性,然而近期研究发现,这些植物多酚物质在抗肿瘤及诱导肿瘤细胞凋亡方面,其促氧化活性可能比其抗氧化活性更加重要,因为ROS可以介导DNA片段化并导致凋亡发生,很多抗肿瘤药物诱导肿瘤细胞凋亡都与引发ROS的产生密切相关,如抗肿瘤药物三氧化二砷、顺铂、以及醌类抗癌药物诱导肿瘤细胞凋亡过程中,胞内ROS的产生都发挥着重要作用。
正常情况下,细胞内ROS的产生与消解处于动态平衡过程中,细胞内环境氧化-还原状态保持相对稳定,而细胞氧化-还原状态对于细胞的生存及各种功能都是至关重要的,破坏细胞氧化-还原状态平衡的主要因素是ROS和GSH,现已知道,低微水平的ROS升高可促进细胞增殖,而较高水平的ROS则引发细胞凋亡,更高水平的ROS则直接导致细胞坏死。多项研究表明,肿瘤细胞内的抗氧化酶如SOD和CAT等,其活性都显著低于正常细胞,肿瘤细胞清除ROS和生成GSH的能力较低,而肿瘤细胞胞内ROS的产生又往往远高于正常细胞,因此肿瘤细胞内存在严重的氧化压力,对ROS十分敏感,ROS对肿瘤细胞具有选择性杀伤力,近年来,人们已经开始开发利用ROS诱导肿瘤细胞凋亡的抗肿瘤新药,而某些膳食多酚化合物,其特性例如与DNA结合、剪切DNA、在过渡金属存在下产生ROS,都与一些抗肿瘤药物相似。由此我们推断,在肿瘤细胞内特别是在细胞关键部位如细胞膜、线粒体膜表面及细胞核内引发ROS,改变细胞氧化-还原状态平衡,对细胞内关键靶点造成氧化压力,从而启动细胞凋亡,这可能是某些植物黄酮抗肿瘤作用的重要机制。
基于以上分析,本课题应用槲皮素等23种分子结构明确、纯度单一的常见植物黄酮,作用于白血病HL-60细胞、乳腺癌MCF-7细胞、前列腺癌PC3细胞等6种不同肿瘤细胞,检测评价不同植物黄酮对肿瘤细胞增殖的影响,分析植物黄酮不同分子结构与其抗肿瘤效应间的结构-效应关系,以及其中的关键结构-效应元件;同时筛选出3种抗肿瘤效应强的植物黄酮和对植物黄酮作用敏感的白血病HL-60细胞作为研究对象,运用流式细胞分析、激光共聚焦扫描显微镜、荧光漂白恢复等先进分子生物学检测分析技术,深入研究植物黄酮诱导肿瘤细胞凋亡过程中,其胞内ROS、GSH和氧化-还原电位的变化,同时对于细胞中最易受ROS攻击的细胞膜和线粒体,本课题进一步研究这些植物黄酮对肿瘤细胞膜流动性和线粒体膜电位的影响,并以抗氧化剂NAC进行干预实验,探讨植物黄酮抗肿瘤的ROS相关作用机制。
本研究主要实验结果和结论如下:
1.细胞增殖状态检测结果表明,被检测的23种植物黄酮大部分对肿瘤细胞增殖都表现出显著抑制作用,并呈现浓度依赖性趋势,但不同植物黄酮之间存在较大差异,同时不同肿瘤细胞对植物黄酮作用表现出不同的敏感性,在被检测的6种肿瘤细胞中,白血病HL-60细胞对于植物黄酮的细胞毒性作用最敏感,植物黄酮3,6-二羟基黄酮和2'-羟基二氢黄酮对6种肿瘤细胞表现出最强的增殖抑制效应,柚皮素和橙皮素对于6种肿瘤细胞均无显著增殖抑制作用,而印棉黄素和桑黄素对于多种肿瘤细胞的增殖具有促进作用,以IC50为标准,比较植物黄酮抑制肿瘤细胞增殖效应的强弱得出以下顺序:3,6-二羟基黄酮> 2'-羟基二氢黄酮>漆树黄酮> 3,7-二羟基黄酮>毛地黄黄酮> 5,7,4'-三羟基黄酮>槲皮素> 6-羟基黄酮> 7-羟基黄酮> 4'-羟基二氢黄酮>高良姜黄素> 3'-甲氧基, 3, 7, 4'-三羟基黄酮>黄芩黄酮>大豆黄素>白杨黄素>杨梅黄酮>染料木黄酮>黄酮>二氢黄酮>柚皮素>橙皮素>桑黄素>印棉黄素。
2.细胞增殖检测结果表明,在被检测的23种植物黄酮中3,6-二羟基黄酮表现出最强的抗肿瘤效应,进一步细胞形态学观察结果表明,10μΜ的3,6-二羟基黄酮处理24 h,6种肿瘤细胞的生长状态和形态均发生显著变化,表现为细胞生长稀疏,排列紊乱,大量细胞皱缩变圆,胞质凝缩,并与其周边细胞分离,细胞贴壁性下降,甚至离开瓶壁漂浮到培养基中,这些形态变化都是凋亡细胞或死亡细胞的表现特征;进一步DAPI染色后荧光显微镜下观察可见,正常肿瘤细胞核呈现弥漫均匀的低强度荧光,出现凋亡形态(固缩形态的亮蓝色颗粒)的比率很低,而3,6-二羟基黄酮处理24 h后,6种肿瘤细胞出现凋亡形态的比率均明显升高;流式细胞凋亡分析结果也表明,10μΜ的3,6-二羟基黄酮处理24 h,6种肿瘤细胞的凋亡率均显著升高。这些实验结果表明,3,6-二羟基黄酮具有很强的抗肿瘤效应,可有效诱导6种肿瘤细胞凋亡。
3.植物黄酮抗肿瘤效应的结构-效应关系分析结果表明,植物黄酮分子中一定数目的羟基(2～4个)、C环2,3位双键、B环定位于2位、3位羟基、6位羟基、B环邻位羟基,对于植物黄酮发挥抗肿瘤效应可能是至关重要的,是其中的关键结构-效应元件,相反,羟基数目的过少或过多、C环2,3位双键的缺失、B环定位于3位(异黄酮结构)、5位羟基和B环间位羟基,则会降低植物黄酮分子的抗肿瘤效应。
4.细胞ROS水平和凋亡检测分析结果表明,HL-60细胞ROS水平显著高于正常人淋巴细胞,而植物黄酮3,6-dihydroxyflavone、luteolin和geraldol作用HL-60细胞,均能引发ROS,造成ROS水平显著升高,并有效诱导HL-60细胞凋亡,而hesperetin和naringenin对HL-60细胞增殖无显著作用的植物黄酮,对HL-60细胞ROS水平无显著影响,且对HL-60细胞凋亡状况亦无显著影响;进一步研究表明,3,6-dihydroxyflavone、luteolin和geraldol均能显著降低HL-60细胞胞内GSH水平,提高GSSG水平,导致HL-60细胞氧化-还原电位显著升高;膜流动性和线粒体膜电位检测结果表明,3种植物黄酮可显著降低HL-60细胞的膜流动性和线粒体膜电位水平。
5. NAC干预实验结果表明,NAC干预可有效阻断植物黄酮3,6-dihydroxyflavone、luteolin和geraldol对HL-60细胞诱发的ROS水平升高、GSH水平下降和细胞氧化-还原电位的升高,以及膜流动性和线粒体膜电位的下降,并部分降低3种植物黄酮对HL-60细胞的增殖抑制作用和凋亡诱导作用。这些实验结果表明,引发ROS和氧化-还原电位水平升高,在3,6-dihydroxyflavone、luteolin和geraldol诱导HL-60细胞凋亡过程中起着重要作用,通过引发ROS和细胞氧化-还原电位水平升高介导肿瘤细胞凋亡,是植物黄酮发挥抗肿瘤作用的一个重要机制。
综上所述,本课题通过检测及比较23种植物黄酮对多种肿瘤细胞的增殖抑制作用,发现3,6-二羟基黄酮具有很强的抗肿瘤活性,结构-效应关系分析表明,一定数目的羟基(2～4个)、C环2,3位双键、B环定位于2位、3位羟基、6位羟基、B环邻位羟基,是植物黄酮发挥抗肿瘤效应的关键结构-效应元件,同时作用机制研究表明,植物黄酮3,6-dihydroxyflavone、luteolin和geraldol可显著提高HL-60细胞ROS水平,降低GSH水平,提高细胞氧化-还原电位,降低细胞膜流动性和线粒体膜电位,诱导细胞凋亡,表明,引发ROS并提高细胞氧化-还原电位从而诱导凋亡,是植物黄酮发挥抗肿瘤作用的重要机制。
Flavonoids are a large class of polyphenolic compounds, which are ubiquitously present in the plant world and our common diet, such as vegetables, fruits and plant-derived beverages. Epidemiological investigations and laboratory studies have indicated several beneficial biological activities of flavonoids, including anti-oxidant, anti-inflammatory, anti-cancer and anti-estrogenic properties. Among these pharmacological properties, there has been an increasing scientific interest in the anti-cancer activity of flavonoids due to their potent inhibition effect on the carcinogenesis, proliferation, migration, invasion, angiogenesis and drug resistance of cancer.
The pharmacological activities of flavonoids depend on their molecular structure; flavonoids with different molecular structure may have different activity. Some structure substituent groups or features may be critical or essential for their certain pharmacological activity, these structure elements are called key structure-activity elements. To analyze the relation between the molecular structure and activity, elucidating the key structure-activity elements, should be useful for revealing the mechanism of certain pharmacological effect of flavonoids, and for guiding the synthesis of potent anti-cancer compounds from flavonoids for potential clinical application. The anti-cancer activity of flavonoids has been an interesting topic around the world, yet most of the studies lay emphasis on some certain flavonoids, the difference and comparison of the anti-cancer activities of flavonoids are neglected. Furthermore, there is a lack in study of the structure-activity relationship for anti-cancer activity of flavonoids, and the key structure-activity elements are still unclear, therefore it is worthwhile to investigate the related topic.
Flavonoids, the dietary phenolics, have been well known as effective anti-oxidant, yet in fact, flavonoids can be both anti-oxidative and pro-oxidative. Studies suggested that under some certain conditions (such as in the presence of O2, transition metals copper and iron), upon oxidation by peroxidase, flavonoids formed phenoxyl radicals and redox cycling of phenolics, which catalyzed GSH or NADH co-oxidation and generated ROS. The beneficial properties of flavonoids are generally believed to reflect their ability to scavenge endogenous ROS. However, the pro-oxidant action of plant-derived phenolics rather than their anti-oxidant action may be an important mechanism for their anti-cancer and apoptosis inducing properties, as ROS can mediate apoptotic DNA fragmentation. Apoptotic DNA fragmentation properties of several anti-cancer drugs, such as arsenic trioxide and cisplatin, are considered to be mediated by ROS.
In normal condition, the production and scavenging of ROS in cells is a dynamic balance, cells maintain a specific redox homeostasis, which plays an important role in the life cycle of cells. ROS and GSH are the key factors influence the redox homeostasis. It has been known that slight elevation of ROS promotes cells proliferation, more high level of ROS induces apoptosis, excessive amount of ROS results in necrosis. Studies indicate that the activities of antioxidases such as SOD and CAT of cancer cells are much lower than that of normal cells, so the ability of scavenging endogenous ROS and producing GSH of cancer cells are much lower. Furthermore, the generation of ROS in cancer cells is higher. Therefore, there is severe oxidation stress in cancer cells; cancer cells are sensitive to ROS, which have selectively cytotoxicities on them. Development of anti-cancer drugs with apoptosis-inducing properties mediated by ROS has currently become a very important topic, and some certain properties of dietary phenolic compounds, such as binding and cleavage of DNA and the generation of ROS in the presence of transition metal ions, are similar to those of known anti-cancer drugs. Therefore, we could raise the hypothesis that flavonoids could induce ROS generation by pro-oxidation in cancer cells, especially in the key points such as lipid and mitochondria membrane, change the redox homeostasis and eventually induce apoptosis, it may be the important mechanism of the anti-cancer activity of flavonoids.
Based on the analysis mentioned above, we used a library of 23 different flavonoids and evaluated cytotoxicity of them in human leukemia HL-60 cells, breast cancer MCF-7 cells, prostatic cancer PC3 cells et al. Structure-activity relationship and the key structure-activity elements were analyzed. Furthermore, we selected out 3 flavonoids with potent cytotoxicity and HL-60 cells to investigate the effect of these flavonoids on the ROS level, GSH level and redox potential of HL-60 cells, by flow cytometric analysis, laser confocal scanning microscopy and fluorescence recovery after photobleaching. We also investigated the effect of flavonoids on the membrane phospholipids mobility and mitochondria membrane potential of HL-60 cells, and observed the influence of NAC pre-treatment on the cytotoxicity and apoptosis induction activity.
The main results and conclusions were summarized as follows:
1. Cells viability assay indicated that most of the 23 flavonoids tested in this study showed significant inhibitory effect on cancer cells proliferation and the effect were enhanced along with increasing concentration. However, the intensity of their effects was different, and HL-60 cells were most sensitive to the cytotoxicity of flavonoids. 3,6-Dihydroxyflavone and 2′-hydroxyflavanone exhibited the most potent cytotoxic effect on all six cells. Flavonoids such as naringenin and hesperetin showed no significant cytotoxic effects on these cancer cells, gossypin and morin promoted some cancer cells viability significantly. The effects of flavonoids on the proliferation of cancer cells were arranged from strong to weak as follow based on IC50: 3,6-dihydroxyflavone > 2'-hydroxyflavanone > fisetin > 3,7-dihydroxyflavone > luteolin > apigenin > quercetin > 6-hydroxyflavone > 7-hydroxyflavone > 4'-hydroxyflavanone > galangin > geraldol > baicalein > daidzein > chrysin > myricetin > genistein > flavone > flavanone > naringenin > hesperetin > morin > gossypin.
2. In order to confirm the potent cytotoxic effect of 3,6-dihydroxyflavone on cancer cells, we examined the morphological changes of cancer cells after the treatment of 3,6-dihydroxyflavone. Treated with 10μΜ3,6-dihydroxyflavone for 24h, dramatic pro-apoptotic morphological changes in comparison with the control were observed in all these six cancer cells, including cell shrinkage and cytoplasmic condensation. Cells retracted from their neighboring cells, rounded up and eventually floated into the media, which is indicative of apoptosis as well. Morphological changes in cell nuclei were determined by fluorescence microscopy after DAPI staining. After 3,6-dihydroxyflavone treatment, the stained nuclei with apparent apoptotic characteristic of condensed nuclei or nuclear fragmentation increased. The apoptosis analysis by flow cytometric assay confirmed the pro-apoptotic effects of 3,6-dihydroxyflavone in all six cancer cells.
3. Structure-activity relationship analysis indicated that some structural properties associated with enhanced cytotoxicity, including appropriate hydroxyl numbers (2～4), the presence of the 2,3-double bond in ring C, ring B attached at position 2, 3-OH, 6-OH and ortho-hydroxylation in ring B, these structural elements are key structure-activity elements for anti-cancer activity of flavonoids. On the contrary, redundant or insufficient hydroxyl numbers, the absence of the 2,3-double bond in ring C, ring B attached at position 3 (iso-flavone structure), 5-OH, and mate-hydroxylation in ring B associated with decreased cytotoxicity.
4. The detection of ROS and apoptosis analysis indicated that the ROS level of HL-60 cells was distinctly higher than that of the normal human lymphocytes, 3,6-dihydroxyflavone, luteolin and geraldol could induce ROS generation and apoptosis. The flavonoids with no significant effect on HL-60 cells viability, hesperetin and naringenin, showed no significant effect on ROS level and apoptosis. Further studies suggested that 3,6-dihydroxyflavone, luteolin and geraldol significantly reduced the GSH level and increased the GSSG level, inducing the elevation of redox potential. Results also indicated that these 3 flavonoids sigcificantly decreased the membrane phospholipids mobility and mitochondria membrane potential of HL-60 cells
5. The addition of NAC completely prevented the generation of intracellular ROS, the decreasing of GSH, the increasing of redox potential, and the decreasing of the membrane phospholipids mobility and mitochondria membrane potential, partially suppressed apoptosis and cell viability reduction induced by 3,6-dihydroxyflavone, luteolin and geraldol. These finding suggested that ROS accumulation and the increasing of redox potential play an important role in pro-apoptosis effect of 3,6-dihydroxyflavone, luteolin and geraldol on HL-60 cells, apoptosis induction mediated by ROS was an critical mechanism of anti-cancer effect of flavonoids.
In all, our study evaluated the cytotoxicity of a library of 23 different flavonoids on six different cancer cells, the findings revealed the potent anti-cancer activity of 3,6-dihydroxylflavone, and the structure-activity relationship analysis elucidated the key structure-activity elements, including appropriate hydroxyl numbers (2～4), the presence of the 2,3-double bond in ring C, ring B attached at position 2, 3-OH, 6-OH and ortho-hydroxylation in ring B. The ROS related mechanism of anti-cancer effects indicated that 3,6-dihydroxyflavone, luteolin and geraldol could significantly elevated the ROS level and redox potential, reduced the GSH level, membrane phospholipids mobility and mitochondria membrane potential, inducing apoptosis in HL-60 cells. These findings indicated that apoptosis induction by elevation of ROS and redox potential plays an important role in anti-cancer effect of flavonoids.
植物黄酮发挥各种药理作用的基础在于其分子结构,不同分子结构的植物黄酮其药理效应可能存在很大差异,而黄酮分子结构中某些特定的取代基或结构特征,对于植物黄酮发挥某一种特定药理效应可能是必需或极重要的,这些结构元件被称为关键结构-效应元件,研究并分析植物黄酮特定分子结构与其特定药理效应之间的构效关系,阐明其中的关键结构-效应元件,对于揭示植物黄酮特定药理学作用的机制,以及寻找高效的植物药和合成新药都具有重要的参考价值。植物黄酮抗肿瘤研究一直为国内外一个研究热点,但绝大多数研究只侧重于某一种植物黄酮的抗肿瘤效应,对不同植物黄酮化合物的抗肿瘤作用的差异研究较少,缺乏相互之间的比较,特别是对于植物黄酮特定分子结构与其抗肿瘤效应之间的构效关系缺乏研究,其中的关键结构-效应元件尚不清楚,因此值得深入探讨。
植物黄酮等多酚类化合物作为优良的天然抗氧化剂已众所周知,但事实上植物黄酮可同时具有抗氧化和促氧化两种相反特性。研究表明,在某些环境下(如O_2大量存在或细胞过氧化物酶活性较高),或某些因素诱导下(如过渡金属Fe或Cu的催化),植物黄酮可被过氧化物酶氧化生成酚自由基,并形成酚氧化反应链,这些酚过氧化物可催化谷胱甘肽或辅酶Ⅰ共氧化并产生活性氧。植物黄酮对疾病的防治作用一般认为在于其优良的抗氧化及清除自由基特性,然而近期研究发现,这些植物多酚物质在抗肿瘤及诱导肿瘤细胞凋亡方面,其促氧化活性可能比其抗氧化活性更加重要,因为ROS可以介导DNA片段化并导致凋亡发生,很多抗肿瘤药物诱导肿瘤细胞凋亡都与引发ROS的产生密切相关,如抗肿瘤药物三氧化二砷、顺铂、以及醌类抗癌药物诱导肿瘤细胞凋亡过程中,胞内ROS的产生都发挥着重要作用。
正常情况下,细胞内ROS的产生与消解处于动态平衡过程中,细胞内环境氧化-还原状态保持相对稳定,而细胞氧化-还原状态对于细胞的生存及各种功能都是至关重要的,破坏细胞氧化-还原状态平衡的主要因素是ROS和GSH,现已知道,低微水平的ROS升高可促进细胞增殖,而较高水平的ROS则引发细胞凋亡,更高水平的ROS则直接导致细胞坏死。多项研究表明,肿瘤细胞内的抗氧化酶如SOD和CAT等,其活性都显著低于正常细胞,肿瘤细胞清除ROS和生成GSH的能力较低,而肿瘤细胞胞内ROS的产生又往往远高于正常细胞,因此肿瘤细胞内存在严重的氧化压力,对ROS十分敏感,ROS对肿瘤细胞具有选择性杀伤力,近年来,人们已经开始开发利用ROS诱导肿瘤细胞凋亡的抗肿瘤新药,而某些膳食多酚化合物,其特性例如与DNA结合、剪切DNA、在过渡金属存在下产生ROS,都与一些抗肿瘤药物相似。由此我们推断,在肿瘤细胞内特别是在细胞关键部位如细胞膜、线粒体膜表面及细胞核内引发ROS,改变细胞氧化-还原状态平衡,对细胞内关键靶点造成氧化压力,从而启动细胞凋亡,这可能是某些植物黄酮抗肿瘤作用的重要机制。
基于以上分析,本课题应用槲皮素等23种分子结构明确、纯度单一的常见植物黄酮,作用于白血病HL-60细胞、乳腺癌MCF-7细胞、前列腺癌PC3细胞等6种不同肿瘤细胞,检测评价不同植物黄酮对肿瘤细胞增殖的影响,分析植物黄酮不同分子结构与其抗肿瘤效应间的结构-效应关系,以及其中的关键结构-效应元件;同时筛选出3种抗肿瘤效应强的植物黄酮和对植物黄酮作用敏感的白血病HL-60细胞作为研究对象,运用流式细胞分析、激光共聚焦扫描显微镜、荧光漂白恢复等先进分子生物学检测分析技术,深入研究植物黄酮诱导肿瘤细胞凋亡过程中,其胞内ROS、GSH和氧化-还原电位的变化,同时对于细胞中最易受ROS攻击的细胞膜和线粒体,本课题进一步研究这些植物黄酮对肿瘤细胞膜流动性和线粒体膜电位的影响,并以抗氧化剂NAC进行干预实验,探讨植物黄酮抗肿瘤的ROS相关作用机制。
本研究主要实验结果和结论如下:
1.细胞增殖状态检测结果表明,被检测的23种植物黄酮大部分对肿瘤细胞增殖都表现出显著抑制作用,并呈现浓度依赖性趋势,但不同植物黄酮之间存在较大差异,同时不同肿瘤细胞对植物黄酮作用表现出不同的敏感性,在被检测的6种肿瘤细胞中,白血病HL-60细胞对于植物黄酮的细胞毒性作用最敏感,植物黄酮3,6-二羟基黄酮和2'-羟基二氢黄酮对6种肿瘤细胞表现出最强的增殖抑制效应,柚皮素和橙皮素对于6种肿瘤细胞均无显著增殖抑制作用,而印棉黄素和桑黄素对于多种肿瘤细胞的增殖具有促进作用,以IC50为标准,比较植物黄酮抑制肿瘤细胞增殖效应的强弱得出以下顺序:3,6-二羟基黄酮> 2'-羟基二氢黄酮>漆树黄酮> 3,7-二羟基黄酮>毛地黄黄酮> 5,7,4'-三羟基黄酮>槲皮素> 6-羟基黄酮> 7-羟基黄酮> 4'-羟基二氢黄酮>高良姜黄素> 3'-甲氧基, 3, 7, 4'-三羟基黄酮>黄芩黄酮>大豆黄素>白杨黄素>杨梅黄酮>染料木黄酮>黄酮>二氢黄酮>柚皮素>橙皮素>桑黄素>印棉黄素。
2.细胞增殖检测结果表明,在被检测的23种植物黄酮中3,6-二羟基黄酮表现出最强的抗肿瘤效应,进一步细胞形态学观察结果表明,10μΜ的3,6-二羟基黄酮处理24 h,6种肿瘤细胞的生长状态和形态均发生显著变化,表现为细胞生长稀疏,排列紊乱,大量细胞皱缩变圆,胞质凝缩,并与其周边细胞分离,细胞贴壁性下降,甚至离开瓶壁漂浮到培养基中,这些形态变化都是凋亡细胞或死亡细胞的表现特征;进一步DAPI染色后荧光显微镜下观察可见,正常肿瘤细胞核呈现弥漫均匀的低强度荧光,出现凋亡形态(固缩形态的亮蓝色颗粒)的比率很低,而3,6-二羟基黄酮处理24 h后,6种肿瘤细胞出现凋亡形态的比率均明显升高;流式细胞凋亡分析结果也表明,10μΜ的3,6-二羟基黄酮处理24 h,6种肿瘤细胞的凋亡率均显著升高。这些实验结果表明,3,6-二羟基黄酮具有很强的抗肿瘤效应,可有效诱导6种肿瘤细胞凋亡。
3.植物黄酮抗肿瘤效应的结构-效应关系分析结果表明,植物黄酮分子中一定数目的羟基(2～4个)、C环2,3位双键、B环定位于2位、3位羟基、6位羟基、B环邻位羟基,对于植物黄酮发挥抗肿瘤效应可能是至关重要的,是其中的关键结构-效应元件,相反,羟基数目的过少或过多、C环2,3位双键的缺失、B环定位于3位(异黄酮结构)、5位羟基和B环间位羟基,则会降低植物黄酮分子的抗肿瘤效应。
4.细胞ROS水平和凋亡检测分析结果表明,HL-60细胞ROS水平显著高于正常人淋巴细胞,而植物黄酮3,6-dihydroxyflavone、luteolin和geraldol作用HL-60细胞,均能引发ROS,造成ROS水平显著升高,并有效诱导HL-60细胞凋亡,而hesperetin和naringenin对HL-60细胞增殖无显著作用的植物黄酮,对HL-60细胞ROS水平无显著影响,且对HL-60细胞凋亡状况亦无显著影响;进一步研究表明,3,6-dihydroxyflavone、luteolin和geraldol均能显著降低HL-60细胞胞内GSH水平,提高GSSG水平,导致HL-60细胞氧化-还原电位显著升高;膜流动性和线粒体膜电位检测结果表明,3种植物黄酮可显著降低HL-60细胞的膜流动性和线粒体膜电位水平。
5. NAC干预实验结果表明,NAC干预可有效阻断植物黄酮3,6-dihydroxyflavone、luteolin和geraldol对HL-60细胞诱发的ROS水平升高、GSH水平下降和细胞氧化-还原电位的升高,以及膜流动性和线粒体膜电位的下降,并部分降低3种植物黄酮对HL-60细胞的增殖抑制作用和凋亡诱导作用。这些实验结果表明,引发ROS和氧化-还原电位水平升高,在3,6-dihydroxyflavone、luteolin和geraldol诱导HL-60细胞凋亡过程中起着重要作用,通过引发ROS和细胞氧化-还原电位水平升高介导肿瘤细胞凋亡,是植物黄酮发挥抗肿瘤作用的一个重要机制。
综上所述,本课题通过检测及比较23种植物黄酮对多种肿瘤细胞的增殖抑制作用,发现3,6-二羟基黄酮具有很强的抗肿瘤活性,结构-效应关系分析表明,一定数目的羟基(2～4个)、C环2,3位双键、B环定位于2位、3位羟基、6位羟基、B环邻位羟基,是植物黄酮发挥抗肿瘤效应的关键结构-效应元件,同时作用机制研究表明,植物黄酮3,6-dihydroxyflavone、luteolin和geraldol可显著提高HL-60细胞ROS水平,降低GSH水平,提高细胞氧化-还原电位,降低细胞膜流动性和线粒体膜电位,诱导细胞凋亡,表明,引发ROS并提高细胞氧化-还原电位从而诱导凋亡,是植物黄酮发挥抗肿瘤作用的重要机制。
Flavonoids are a large class of polyphenolic compounds, which are ubiquitously present in the plant world and our common diet, such as vegetables, fruits and plant-derived beverages. Epidemiological investigations and laboratory studies have indicated several beneficial biological activities of flavonoids, including anti-oxidant, anti-inflammatory, anti-cancer and anti-estrogenic properties. Among these pharmacological properties, there has been an increasing scientific interest in the anti-cancer activity of flavonoids due to their potent inhibition effect on the carcinogenesis, proliferation, migration, invasion, angiogenesis and drug resistance of cancer.
The pharmacological activities of flavonoids depend on their molecular structure; flavonoids with different molecular structure may have different activity. Some structure substituent groups or features may be critical or essential for their certain pharmacological activity, these structure elements are called key structure-activity elements. To analyze the relation between the molecular structure and activity, elucidating the key structure-activity elements, should be useful for revealing the mechanism of certain pharmacological effect of flavonoids, and for guiding the synthesis of potent anti-cancer compounds from flavonoids for potential clinical application. The anti-cancer activity of flavonoids has been an interesting topic around the world, yet most of the studies lay emphasis on some certain flavonoids, the difference and comparison of the anti-cancer activities of flavonoids are neglected. Furthermore, there is a lack in study of the structure-activity relationship for anti-cancer activity of flavonoids, and the key structure-activity elements are still unclear, therefore it is worthwhile to investigate the related topic.
Flavonoids, the dietary phenolics, have been well known as effective anti-oxidant, yet in fact, flavonoids can be both anti-oxidative and pro-oxidative. Studies suggested that under some certain conditions (such as in the presence of O2, transition metals copper and iron), upon oxidation by peroxidase, flavonoids formed phenoxyl radicals and redox cycling of phenolics, which catalyzed GSH or NADH co-oxidation and generated ROS. The beneficial properties of flavonoids are generally believed to reflect their ability to scavenge endogenous ROS. However, the pro-oxidant action of plant-derived phenolics rather than their anti-oxidant action may be an important mechanism for their anti-cancer and apoptosis inducing properties, as ROS can mediate apoptotic DNA fragmentation. Apoptotic DNA fragmentation properties of several anti-cancer drugs, such as arsenic trioxide and cisplatin, are considered to be mediated by ROS.
In normal condition, the production and scavenging of ROS in cells is a dynamic balance, cells maintain a specific redox homeostasis, which plays an important role in the life cycle of cells. ROS and GSH are the key factors influence the redox homeostasis. It has been known that slight elevation of ROS promotes cells proliferation, more high level of ROS induces apoptosis, excessive amount of ROS results in necrosis. Studies indicate that the activities of antioxidases such as SOD and CAT of cancer cells are much lower than that of normal cells, so the ability of scavenging endogenous ROS and producing GSH of cancer cells are much lower. Furthermore, the generation of ROS in cancer cells is higher. Therefore, there is severe oxidation stress in cancer cells; cancer cells are sensitive to ROS, which have selectively cytotoxicities on them. Development of anti-cancer drugs with apoptosis-inducing properties mediated by ROS has currently become a very important topic, and some certain properties of dietary phenolic compounds, such as binding and cleavage of DNA and the generation of ROS in the presence of transition metal ions, are similar to those of known anti-cancer drugs. Therefore, we could raise the hypothesis that flavonoids could induce ROS generation by pro-oxidation in cancer cells, especially in the key points such as lipid and mitochondria membrane, change the redox homeostasis and eventually induce apoptosis, it may be the important mechanism of the anti-cancer activity of flavonoids.
Based on the analysis mentioned above, we used a library of 23 different flavonoids and evaluated cytotoxicity of them in human leukemia HL-60 cells, breast cancer MCF-7 cells, prostatic cancer PC3 cells et al. Structure-activity relationship and the key structure-activity elements were analyzed. Furthermore, we selected out 3 flavonoids with potent cytotoxicity and HL-60 cells to investigate the effect of these flavonoids on the ROS level, GSH level and redox potential of HL-60 cells, by flow cytometric analysis, laser confocal scanning microscopy and fluorescence recovery after photobleaching. We also investigated the effect of flavonoids on the membrane phospholipids mobility and mitochondria membrane potential of HL-60 cells, and observed the influence of NAC pre-treatment on the cytotoxicity and apoptosis induction activity.
The main results and conclusions were summarized as follows:
1. Cells viability assay indicated that most of the 23 flavonoids tested in this study showed significant inhibitory effect on cancer cells proliferation and the effect were enhanced along with increasing concentration. However, the intensity of their effects was different, and HL-60 cells were most sensitive to the cytotoxicity of flavonoids. 3,6-Dihydroxyflavone and 2′-hydroxyflavanone exhibited the most potent cytotoxic effect on all six cells. Flavonoids such as naringenin and hesperetin showed no significant cytotoxic effects on these cancer cells, gossypin and morin promoted some cancer cells viability significantly. The effects of flavonoids on the proliferation of cancer cells were arranged from strong to weak as follow based on IC50: 3,6-dihydroxyflavone > 2'-hydroxyflavanone > fisetin > 3,7-dihydroxyflavone > luteolin > apigenin > quercetin > 6-hydroxyflavone > 7-hydroxyflavone > 4'-hydroxyflavanone > galangin > geraldol > baicalein > daidzein > chrysin > myricetin > genistein > flavone > flavanone > naringenin > hesperetin > morin > gossypin.
2. In order to confirm the potent cytotoxic effect of 3,6-dihydroxyflavone on cancer cells, we examined the morphological changes of cancer cells after the treatment of 3,6-dihydroxyflavone. Treated with 10μΜ3,6-dihydroxyflavone for 24h, dramatic pro-apoptotic morphological changes in comparison with the control were observed in all these six cancer cells, including cell shrinkage and cytoplasmic condensation. Cells retracted from their neighboring cells, rounded up and eventually floated into the media, which is indicative of apoptosis as well. Morphological changes in cell nuclei were determined by fluorescence microscopy after DAPI staining. After 3,6-dihydroxyflavone treatment, the stained nuclei with apparent apoptotic characteristic of condensed nuclei or nuclear fragmentation increased. The apoptosis analysis by flow cytometric assay confirmed the pro-apoptotic effects of 3,6-dihydroxyflavone in all six cancer cells.
3. Structure-activity relationship analysis indicated that some structural properties associated with enhanced cytotoxicity, including appropriate hydroxyl numbers (2～4), the presence of the 2,3-double bond in ring C, ring B attached at position 2, 3-OH, 6-OH and ortho-hydroxylation in ring B, these structural elements are key structure-activity elements for anti-cancer activity of flavonoids. On the contrary, redundant or insufficient hydroxyl numbers, the absence of the 2,3-double bond in ring C, ring B attached at position 3 (iso-flavone structure), 5-OH, and mate-hydroxylation in ring B associated with decreased cytotoxicity.
4. The detection of ROS and apoptosis analysis indicated that the ROS level of HL-60 cells was distinctly higher than that of the normal human lymphocytes, 3,6-dihydroxyflavone, luteolin and geraldol could induce ROS generation and apoptosis. The flavonoids with no significant effect on HL-60 cells viability, hesperetin and naringenin, showed no significant effect on ROS level and apoptosis. Further studies suggested that 3,6-dihydroxyflavone, luteolin and geraldol significantly reduced the GSH level and increased the GSSG level, inducing the elevation of redox potential. Results also indicated that these 3 flavonoids sigcificantly decreased the membrane phospholipids mobility and mitochondria membrane potential of HL-60 cells
5. The addition of NAC completely prevented the generation of intracellular ROS, the decreasing of GSH, the increasing of redox potential, and the decreasing of the membrane phospholipids mobility and mitochondria membrane potential, partially suppressed apoptosis and cell viability reduction induced by 3,6-dihydroxyflavone, luteolin and geraldol. These finding suggested that ROS accumulation and the increasing of redox potential play an important role in pro-apoptosis effect of 3,6-dihydroxyflavone, luteolin and geraldol on HL-60 cells, apoptosis induction mediated by ROS was an critical mechanism of anti-cancer effect of flavonoids.
In all, our study evaluated the cytotoxicity of a library of 23 different flavonoids on six different cancer cells, the findings revealed the potent anti-cancer activity of 3,6-dihydroxylflavone, and the structure-activity relationship analysis elucidated the key structure-activity elements, including appropriate hydroxyl numbers (2～4), the presence of the 2,3-double bond in ring C, ring B attached at position 2, 3-OH, 6-OH and ortho-hydroxylation in ring B. The ROS related mechanism of anti-cancer effects indicated that 3,6-dihydroxyflavone, luteolin and geraldol could significantly elevated the ROS level and redox potential, reduced the GSH level, membrane phospholipids mobility and mitochondria membrane potential, inducing apoptosis in HL-60 cells. These findings indicated that apoptosis induction by elevation of ROS and redox potential plays an important role in anti-cancer effect of flavonoids.
引文
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