天然产物的抗真菌和抗肿瘤活性及机制研究
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摘要
植物药一直是天然药物的重要来源,也是人类防病治病的主要来源。真菌感染和恶性肿瘤的发病率呈逐年上升趋势,并且临床上真菌耐药与肿瘤耐药时有发生,促使人们将希望寄托于寻找新型的天然抗菌和抗癌药物,以期发现疗效更好或具有新靶点的化合物。·目前为止,世界上许多国家对抗真菌和抗肿瘤新药的研究投入大量的人力和财力。自然界数以百万计的动植物、微生物和海洋生物是新药研发的重要源泉。地衣(lichen)是植物界一个特殊的类群,是真菌(fungi)和藻类(algae)高度结合的共生复合体。近几年的文献报道从地衣植物中分离得到了许多具有活性的新化合物。通过对从云南光肺衣中分离得到的retigeric acid B(RAB)抗白色念珠菌活性的研究,发现此化合物具有中等的抗真菌活性,最低抑制浓度为8～16μg/ml。用棋盘式微量稀释法评价RAB与氟康唑、酮康唑、伊曲康唑药物联合用药的关系,药物相互作用采用Loewe additivity (LA)模型的非参数法采用分数抑菌浓度指数(fractional inhibitory concentration index, FICI和基于Blics independence (BI)理论的AE模型评价。当RAB与氟康唑、酮康唑、伊曲康唑药物联合用药时,对临床分离的白色念珠菌具有协同的抗真菌活性。它与唑类联用后,唑类对耐药菌株最低抑制浓度有的能下降1000倍以上。FICI和AE模型两种评价方法一致性良好,对耐药菌株,RAB与唑类的联合用药都具有协同作用；对敏感菌株,RAB与唑类的联合用药具有协同或者不相关,无拮抗作用。本文还应用琼脂扩散法和时间-杀菌曲线法测定RAB与唑类药物对耐药白色念珠菌CA10的联合抗真菌作用。在琼脂扩散法实验中,联合用药的抑菌圈明显比单独用药的抑菌圈大而且干净。时间-杀菌曲线采用活菌计数法和XTT法评价活菌数,结果所示所测浓度RAB与唑类单用都只有很弱或者几乎没有抗菌活性,而联合用药后与单用药相比活菌数产生了>2Log10CFU/ml的降低,证明RAB与唑类动态联合抗真菌作用同样具有协同效果。研究它们的协同机制,采用荧光分光光度法和流式细胞仪测定RAB对罗丹明123的累积、吸收和外排,发现RAB能显著增加罗丹明123的累积。用荧光定量PCR测定外排泵基因CDR1的表达,发现RAB能下调耐药菌CA10的CDR1的表达,对敏感菌的CDR1表达影响不大。用荧光显微镜观察RAB对菌株CaSA1(Cdrlp-GFP)的影响,加入RAB后,绿色荧光分布不均匀,比对照组荧光强度明显减弱,而且部分细胞膜上无绿色荧光。通过上述实验推测RAB能抑制外排泵的活性从而增加联用药物的浓度。此外本文还测定了RAB对真菌细胞膜主要成分麦角甾醇含量的影响。麦角甾醇和24(28)-去氢麦角甾醇(dehydroergosterol,DHE)在281.5nm处都有吸收峰,但是在230nm处只有24(28) - DHE有吸收峰。利用这个特点,实验采用皂化的方法提取真菌细胞膜甾醇成分,并用紫外分析法测定。结果显示RAB具有降低麦角甾醇的作用,麦角甾醇的缺失会影响真菌膜的流动性和通透性。同时用荧光定量PCR检测了RAB对羊毛甾醇α-去甲基化酶基因(ERG11)的影响。RAB能降低敏感和耐药菌ERG11的表达,敏感菌降低0.42倍,耐药菌降低0.23倍。电镜观察,与正常菌超微结构相比,RAB作用的细胞壁与细胞膜皱缩不完整,细胞膜与细胞壁结构松散,内容物外泄,细胞体积明显变大。通过检测RAB对药物外排泵功能的影响、麦角甾醇的含量的影响及重要耐药相关基因,RAB协同抗白色念珠菌的可能机制是：(1)通过抑制外排泵的活性,从而增加唑类药物的细胞内累积从而发挥抗菌活性；(2)和唑类具有相同的抑制麦角甾醇合生物合成途径。(3)通过对膜结构的破坏增加唑类的渗透,增加累积。
在抗肿瘤活性研究方面,论文主要研究了从中药茄属类植物龙葵中分离得到的甾体生物碱类化合物solamargine (SM)、solasonine、β2-solamargine和它们的苷元solasodine的抗肿瘤活性,分析了它们的活性与糖链的关系。它们的活性大小分别是SM>solasonine>β2-solamargine>solasodine,SM结构中含有2个鼠李糖,与其它两个甾体皂苷(solasonine和β2-solamargine)相比,它所表现的是活性最好和细胞内累积含量最高,而对于正常细胞,它的细胞毒性明显低于肿瘤细胞。含糖侧链的甾体皂苷活性强于其相应的苷元；含三糖侧链的甾体皂苷(SM和solasonine)活性大于含二糖侧链的甾体皂苷(β2-solamargine)。其中两个含三糖侧链的甾体皂苷,鼠李糖多(SM)的活性强于鼠李糖少(solasonine)的。SM对正常细胞视网膜上皮细胞RPE1和肾系膜细胞MC的杀伤作用比肿瘤细胞弱,暗示SM对细胞的杀伤具有一定的选择性。并且SM对肿瘤耐药细胞K562/A02和KB/VCR细胞同样表现出较强的细胞毒作用。对K562/A02的细胞毒性甚至强于K562细胞。对于活性最好的SM,进一步研究了SM的诱导肿瘤细胞死亡的机制。低浓度的SM能诱导肿瘤细胞凋亡,而高浓度的SM则能使肿瘤细胞发生胀亡。我们首先用DAPI荧光染色观察不同浓度梯度的SM对细胞核的影响；然后用Annexin V/PI双染并用流式细胞仪测定凋亡率。在凋亡途径的研究中,我们观察到,SM能诱导早期溶酶体膜的通透性增加,表现为溶酶体体积肿胀,组织蛋白酶B的释放以及在胞液中的激活。溶酶体通过释放溶酶体酶进入胞质降解蛋白质等参与凋亡。释放的溶酶体组织蛋白酶能通过剪切Bcl-2家族,然后转移到线粒体,引起一系列的促凋亡反应,溶酶体组织蛋白酶也可以激活Bax引起线粒体膜通透性增高,释放凋亡诱导因子细胞色素C激活caspase,导致细胞发生凋亡。SM通过溶酶体-线粒体途径诱导肿瘤细胞凋亡。
对于高浓度IC80的SM能迅速破坏细胞膜,我们采用LDH、核酸泄漏的测定方法和PI的荧光染色法来评价。实验结果表明SM对肿瘤细胞K562和KB细胞膜能诱导通透性增加的作用。通过活细胞实时观察加药处理后,细胞的形态变化。肿瘤细胞随着药物的刺激,细胞膜出现大小不一的泡,然后细胞体积增大,最后泡崩裂,胞内容物溢出,细胞溶解而死亡,整个细胞死亡过程非常迅速而且剧烈。对于SM能使细胞膜通透性增加,溶剂分子大量进入细胞,将细胞膜胀破释放出细胞内容物。对此实验采用含不同分子量的聚乙二醇的培养基来测定SM引起的膜孔径大小的变化,从而判断SM对细胞膜的破坏程度。孔径越大,对膜损伤也越大。细胞膜具有选择通透性,水分子可以自由通过细胞膜,溶剂分子的相对分子质量越大,进入细胞就慢,发生细胞膨胀所需的时间也长。当聚乙二醇的分子量≥3350时,在所测定时间内(10min)能明显抑制细胞膜出泡,并且当聚乙二醇与SM共培养时,随着聚乙二醇分子量的增加,SM对肿瘤细胞的抑制率下降,聚乙二醇1000对SM的细胞毒性没有影响。SM能增加细胞内游离钙离子的浓度,通过用BAPTA-AM螯合细胞内游离钙后,一定程度上延缓了细胞膜出泡的时间：而通过用EGTA螯合培养基里的钙离子从而阻止胞外钙离子进入细胞,但是也只是短时间的阻止细胞膜出泡,所以SM诱导膜出泡不依赖于钙离子。SM能降低细胞内ATP水平、降解细胞骨架,对细胞周期没有影响。SM引起肿瘤细胞发生胀亡的原因不是单一的,而是多种因素共同作用的结果。
此外对SM的亚细胞分布进行了研究,采用磁色谱法分离溶酶体和采用蔗糖密度梯度离心分离线粒体并且利用液质联用测定化合物在细胞器的累积。有研究表明受体介导内吞会引起溶酶体碱化,配体与细胞膜上受体结合后会形成内吞体,而内吞体与溶酶体融合,导致溶酶体体积增加,从而使溶酶体中pH上升。本实验中,通过分离亚细胞器并且测定各个细胞器内的药物含量,发现在耐药细胞中,SM能优先累积于溶酶体内,可能由于耐药细胞溶酶体的pH较低,SM又是一个甾体类的生物碱,具有弱碱性,从而被离子化,而不易通过脂质层；而在敏感细胞中,SM在线粒体与溶酶体内的含量没有明显的差异,可能由于敏感细胞溶酶体pH比耐药细胞高,SM离子化较少。
本论文在抗真菌方面首次研究了retigeric acid B的抗真菌作用,并且能逆转真菌耐药,可作为临床唑类抗真菌药物的增强剂；抗肿瘤方面,首次报道了SM能通过溶酶体-线粒体途径诱发肿瘤细胞发生凋亡；并且当浓度为IC80(10μM)的SM能迅速诱导肿瘤细胞发生胀亡。细胞凋亡是程序性细胞死亡的过程,细胞凋亡后对周围组织影响不大；而细胞胀亡因细胞膜的破坏导致内容物的外泄,会引起周围组织炎症反应发生,所以只有合理用药才能控制好药物的毒性而达到更好的抗肿瘤效果。论文还对SM的亚细胞分布进行了研究,发现该化合物能优先累积于耐药细胞的溶酶体中,为研究该化合物的作用靶点及吸收方式提供了依据。
Natural plant has been an important source of natural medicines, but also a major source of treating and preventing human disease. The incidence of fungal infections and cancer are increasing every year. An increase number of reports of clinical resistance to antifungal agents and anticancer agents highlight the need for searching for new antifungal and anticancer drugs which may have a new target and treat better. So far the research on antifungal and anticancer drugs has been supported by many countries. Millions of plants, animals, microorganisms, and marine organisms are an important source of new drug discovery. Lichens are quite a special large group in the the plant kingdom as high degree of integration of the symbiotic complex between fungi and algae. Recently, a lot of new bioactive compounds have been isolated as reported in the literature. The vitro antifungal activity of retigeric acid B (RAB), a pentacyclic triterpenoid from the lichen species Lobaria kurokawae, was evaluated alone and in combination with fluconazole, ketoconazole, and itraconazole against Candida albicans using checkerboard microdilution, agar diffusion assay, and time-killing tests. The minimum inhibitory concentrations (MICs) for RAB against ten different C. albicans isolates ranged from 8 to 16μg/ml.A synergistic action of RAB and azole was observed in azole-resistant strains, whereas synergistic or indifferent effects observed in azole-sensitive strains, when interpreted by separate approach of FICI (fractional inhibitory concentration index) and AE model (difference between the predicted and measured fungal growth percentages). In agar diffusion assay, the combination yielded significantly clearer and larger zones than those of either drug alone on the plain agar plate. In time-killing tests, we used both colony counts and a colorimetric assay to evaluate the combinational antifungal effects of RAB and azoles. For the tested concentration of RAB and azole hardly have activity against C. albicans but the combination yielded a>2log10CFU/ml decrease compared with either drug used alone which further confirmed their synergistic interactions. These findings suggest natural products of RAB may play a certain role in increasing the susceptibilities of azole-resistant C. albicans strains. Next we studied the underlying synergistic antifungal mechanisms of RAB in combination with azoles against C. albicans. Increased accumulation of rhodamine 123 (Rh123) in C. albicans was measured by both spectrophotometric method and flow cytometry. The inhibitory properties to the drug efflux of C. albicans were determined spectrophotometrically. A special indicator organism, CASA1 which has a green fluorescent protein gene inserted in place of one allele of the CDR1 structural gene, was used to investigate regulation of CDR1. After treated by RAB, the distribution of green fluorescence was changed, the intensity of fluorescence was decreased compared with the control, and some of them lost the green fluorescence. The downregulation expression level of CDR1 was detected by real-time reverse transcription polymerase chain reaction. Above all, RAB synergize the antifungal effect of azoles against C. albicans by inhibiting efflux pump activity. Cellular ergosterol synthesis was measured using its unique spectrophotetric absorbance profile. Both ergosterol and 24(28)-DHE absorb at 281.5 nm, whereas only 24(28)-DHE absorbs at 230 nm. The decreased cellular ergosterol synthesis was measured using its unique spectrophotetric absorbance profile and we found that when cells were treated with RAB, the expression of ERG11 was downregulated and ergosterol level was decreased. ERG11 expression in C. albicans after treatment by 16μg/ml RAB was markedly lower than untreated isolates (0.42-fold for azole-sensitive strain and 0.23-fold for azole-resistant strain, respectively). Low ergosterol content will enhance the membrane fluidity. An increase in membrane fluidity directly results in increased passive diffusion of drugs and sensitization of Candida cells to antifungals. Transmission electron microscopy investigation found the wrinkled cell membrane and the impaired cell wall due to RAB treatment. RAB synergize the antifungal effect of azoles against C. albicans by inhibiting efflux pump activity, targeting the ergosterol biosynthesis pathway resulted ergosterol depletion, and impairing the function of fungal cell membranes and increasing penetration of an antifungal agent.
About the anticancer activity, the paper studied the activity of steroidal alkaloid glycoside isolated from Chinese herb Solanum Solanum nigrum L. Solamargine (SM), solasonine,β2-solamargine, and solasodine have the same aglycon solanidine, but different saccharide chains. We discussed the structural activity relationships between the steroidal alkaloidal saponins and inhibition of the growth of cancer cells. SM with a two-rhamnosyl on the trisaccharide chain achieved higher intracellular concentrations and was potently toxic. As compared with the tumor cell lines, SM had a lower cytotoxicity on the normal cell retinal pigment epithelial cell line RPE-1 and mesangial cells MC. The cytotoxicity of SM did not correlate with the expression level of the multidrug resistance MDR1 and had the strong cytotoxicity on K562/A02 and KB/VCR. Solasonine, which has a trisacharide chain, has also exhibited moderate cytotoxicity, while other two compounds, without the trisacharide chain, had no anticancer activity. These studies revealed the trisaccharide chain was critical for activity in these steroidal alkaloid saponins. It is likely that apoptosis can be induced by low doses of SM, and oncosis by high doses, both types of cell death are induced by intermediate concentration of SM. Apoptosis was evaluated by DAPI staining and annexin V/PI double staining. Further investigation with human K562 leukemia cells found that SM could induce an early lysosomal rupture within 2h as assessed by acridine-orange relocation and alkalinization of lysosomes. Intracellular lysosomal rupture is also confirmed with the release of cathepsin B to cytosol detected by western blot. Subsequent mitochondrial damage including mitochondrial membrane permeabilization detected by decrease membrane potential as well as the release of cytochrome c from mitochondria was also observed. The down-expression of Bcl-2, up-regulation of Bax, caspase-3 and caspase-9 activities followed by above changes revealed that the cytoxicity of SM was involved in a lysosomal-mitochondrial death pathway induced by SM.
Cell membrane integrity was assessed by detecting the leakage of cytoplasmic content, the release of lactate dehydrogenase (LDH), and the uptake of propidium iodide (PI). The rapid ability of SM (IC80) to make PI permeate into tumor cells, LDH release, and leakage of cytoplasmic content at the same rate (within minutes), suggests a killing mechanism that involves plasma membrane perturbation. We use whole-cell recording to measure the time courses of membrane blebbing and disruption in human K562 leukemia and squamous cell carcinoma KB cells. SM induced membrane blebbing within 5 min of sustained application. Both chelating extracellular calcium with EGTA and clamping intracellular calcium concentrations with a high concentration of the cell-permeable chelator BAPTA-AM did not prevent blebbing. Polyethylene glycols having molecular weights≥3350 blocked membrane blebbing. We also evaluated the effects of PEGs of various molecular weights on antitumor effect of SM. PEG 1000 had no effect on antitumor effect of SM. Chelating extracellular calcium with EGTA did not prevent blebbing after a delay, showing that the formation of blebs does not depend on the influx of calcium. Blebbing was also not affected when the intracellular calcium concentration was clamped by the cell-permeable chelator BAPTA-AM. Blebbing is independent of calcium. SM reduced intracellular ATP levels, disrupted the cytoskeletal systems, and had no effect on cell cycle.
In addition, the quantity drugs associated with intracellular compartments was studied. We used a magnetic capture technique that allows for isolation of lysosomes and sucrose density gradient centrifugation for isolation of mitochondrial. After incubation with SM, cells were separated into fractions containing cytosol, lysosomes, and mitochondria and quantitation of compounds by LC/MS/MS. It is reported that receptor-mediated endocytosis cause lysosomal alkalinization and swollen. The amounts of SM that accumulated in the lysosomes and mitochondrial were determined. SM was found to preferentially accumulate within lysosomes in drug-resistant cells. These results suggest the internalization of SM in cancer cells may be related to rhamnose receptor-mediated endocytosis through endosomes, leading to localization in the lysosomes. In addition, the lumenal PH of lysosomes is known to be considerably lower in MDR cells, resulting in an enhanced lysosome-to-cytosol pH differential. SM, as a weakly basic compound, may become ionized and unable to diffuse back through the lipid monolayer of lysosomal membrane.
In this thesis, we described the antifungal activity of RAB and its capacity to reverse azole resistance. It can be used clinically as an antifungal agent to potentiate azole antifungal agents. About the anticancer activity, it's the first report SM (IC80) can induce oncosis on cancer cell. Apoptosis is the process of programmed cell death and has little effect upon surrounding tissue. However, oncosis resulting from cell membrane damage and the leakage of contents can cause inflammation of surrounding tissue. Rational use of anticancer agents will reduce the dose toxicity and achieve a better anticancer effect. The intracellular distribution of SM was also studied in this paper. SM was found to preferentially accumulate within lysosomes in drug-resistant cells, which is important to drug delivery and its target research
在抗肿瘤活性研究方面,论文主要研究了从中药茄属类植物龙葵中分离得到的甾体生物碱类化合物solamargine (SM)、solasonine、β2-solamargine和它们的苷元solasodine的抗肿瘤活性,分析了它们的活性与糖链的关系。它们的活性大小分别是SM>solasonine>β2-solamargine>solasodine,SM结构中含有2个鼠李糖,与其它两个甾体皂苷(solasonine和β2-solamargine)相比,它所表现的是活性最好和细胞内累积含量最高,而对于正常细胞,它的细胞毒性明显低于肿瘤细胞。含糖侧链的甾体皂苷活性强于其相应的苷元；含三糖侧链的甾体皂苷(SM和solasonine)活性大于含二糖侧链的甾体皂苷(β2-solamargine)。其中两个含三糖侧链的甾体皂苷,鼠李糖多(SM)的活性强于鼠李糖少(solasonine)的。SM对正常细胞视网膜上皮细胞RPE1和肾系膜细胞MC的杀伤作用比肿瘤细胞弱,暗示SM对细胞的杀伤具有一定的选择性。并且SM对肿瘤耐药细胞K562/A02和KB/VCR细胞同样表现出较强的细胞毒作用。对K562/A02的细胞毒性甚至强于K562细胞。对于活性最好的SM,进一步研究了SM的诱导肿瘤细胞死亡的机制。低浓度的SM能诱导肿瘤细胞凋亡,而高浓度的SM则能使肿瘤细胞发生胀亡。我们首先用DAPI荧光染色观察不同浓度梯度的SM对细胞核的影响；然后用Annexin V/PI双染并用流式细胞仪测定凋亡率。在凋亡途径的研究中,我们观察到,SM能诱导早期溶酶体膜的通透性增加,表现为溶酶体体积肿胀,组织蛋白酶B的释放以及在胞液中的激活。溶酶体通过释放溶酶体酶进入胞质降解蛋白质等参与凋亡。释放的溶酶体组织蛋白酶能通过剪切Bcl-2家族,然后转移到线粒体,引起一系列的促凋亡反应,溶酶体组织蛋白酶也可以激活Bax引起线粒体膜通透性增高,释放凋亡诱导因子细胞色素C激活caspase,导致细胞发生凋亡。SM通过溶酶体-线粒体途径诱导肿瘤细胞凋亡。
对于高浓度IC80的SM能迅速破坏细胞膜,我们采用LDH、核酸泄漏的测定方法和PI的荧光染色法来评价。实验结果表明SM对肿瘤细胞K562和KB细胞膜能诱导通透性增加的作用。通过活细胞实时观察加药处理后,细胞的形态变化。肿瘤细胞随着药物的刺激,细胞膜出现大小不一的泡,然后细胞体积增大,最后泡崩裂,胞内容物溢出,细胞溶解而死亡,整个细胞死亡过程非常迅速而且剧烈。对于SM能使细胞膜通透性增加,溶剂分子大量进入细胞,将细胞膜胀破释放出细胞内容物。对此实验采用含不同分子量的聚乙二醇的培养基来测定SM引起的膜孔径大小的变化,从而判断SM对细胞膜的破坏程度。孔径越大,对膜损伤也越大。细胞膜具有选择通透性,水分子可以自由通过细胞膜,溶剂分子的相对分子质量越大,进入细胞就慢,发生细胞膨胀所需的时间也长。当聚乙二醇的分子量≥3350时,在所测定时间内(10min)能明显抑制细胞膜出泡,并且当聚乙二醇与SM共培养时,随着聚乙二醇分子量的增加,SM对肿瘤细胞的抑制率下降,聚乙二醇1000对SM的细胞毒性没有影响。SM能增加细胞内游离钙离子的浓度,通过用BAPTA-AM螯合细胞内游离钙后,一定程度上延缓了细胞膜出泡的时间：而通过用EGTA螯合培养基里的钙离子从而阻止胞外钙离子进入细胞,但是也只是短时间的阻止细胞膜出泡,所以SM诱导膜出泡不依赖于钙离子。SM能降低细胞内ATP水平、降解细胞骨架,对细胞周期没有影响。SM引起肿瘤细胞发生胀亡的原因不是单一的,而是多种因素共同作用的结果。
此外对SM的亚细胞分布进行了研究,采用磁色谱法分离溶酶体和采用蔗糖密度梯度离心分离线粒体并且利用液质联用测定化合物在细胞器的累积。有研究表明受体介导内吞会引起溶酶体碱化,配体与细胞膜上受体结合后会形成内吞体,而内吞体与溶酶体融合,导致溶酶体体积增加,从而使溶酶体中pH上升。本实验中,通过分离亚细胞器并且测定各个细胞器内的药物含量,发现在耐药细胞中,SM能优先累积于溶酶体内,可能由于耐药细胞溶酶体的pH较低,SM又是一个甾体类的生物碱,具有弱碱性,从而被离子化,而不易通过脂质层；而在敏感细胞中,SM在线粒体与溶酶体内的含量没有明显的差异,可能由于敏感细胞溶酶体pH比耐药细胞高,SM离子化较少。
本论文在抗真菌方面首次研究了retigeric acid B的抗真菌作用,并且能逆转真菌耐药,可作为临床唑类抗真菌药物的增强剂；抗肿瘤方面,首次报道了SM能通过溶酶体-线粒体途径诱发肿瘤细胞发生凋亡；并且当浓度为IC80(10μM)的SM能迅速诱导肿瘤细胞发生胀亡。细胞凋亡是程序性细胞死亡的过程,细胞凋亡后对周围组织影响不大；而细胞胀亡因细胞膜的破坏导致内容物的外泄,会引起周围组织炎症反应发生,所以只有合理用药才能控制好药物的毒性而达到更好的抗肿瘤效果。论文还对SM的亚细胞分布进行了研究,发现该化合物能优先累积于耐药细胞的溶酶体中,为研究该化合物的作用靶点及吸收方式提供了依据。
Natural plant has been an important source of natural medicines, but also a major source of treating and preventing human disease. The incidence of fungal infections and cancer are increasing every year. An increase number of reports of clinical resistance to antifungal agents and anticancer agents highlight the need for searching for new antifungal and anticancer drugs which may have a new target and treat better. So far the research on antifungal and anticancer drugs has been supported by many countries. Millions of plants, animals, microorganisms, and marine organisms are an important source of new drug discovery. Lichens are quite a special large group in the the plant kingdom as high degree of integration of the symbiotic complex between fungi and algae. Recently, a lot of new bioactive compounds have been isolated as reported in the literature. The vitro antifungal activity of retigeric acid B (RAB), a pentacyclic triterpenoid from the lichen species Lobaria kurokawae, was evaluated alone and in combination with fluconazole, ketoconazole, and itraconazole against Candida albicans using checkerboard microdilution, agar diffusion assay, and time-killing tests. The minimum inhibitory concentrations (MICs) for RAB against ten different C. albicans isolates ranged from 8 to 16μg/ml.A synergistic action of RAB and azole was observed in azole-resistant strains, whereas synergistic or indifferent effects observed in azole-sensitive strains, when interpreted by separate approach of FICI (fractional inhibitory concentration index) and AE model (difference between the predicted and measured fungal growth percentages). In agar diffusion assay, the combination yielded significantly clearer and larger zones than those of either drug alone on the plain agar plate. In time-killing tests, we used both colony counts and a colorimetric assay to evaluate the combinational antifungal effects of RAB and azoles. For the tested concentration of RAB and azole hardly have activity against C. albicans but the combination yielded a>2log10CFU/ml decrease compared with either drug used alone which further confirmed their synergistic interactions. These findings suggest natural products of RAB may play a certain role in increasing the susceptibilities of azole-resistant C. albicans strains. Next we studied the underlying synergistic antifungal mechanisms of RAB in combination with azoles against C. albicans. Increased accumulation of rhodamine 123 (Rh123) in C. albicans was measured by both spectrophotometric method and flow cytometry. The inhibitory properties to the drug efflux of C. albicans were determined spectrophotometrically. A special indicator organism, CASA1 which has a green fluorescent protein gene inserted in place of one allele of the CDR1 structural gene, was used to investigate regulation of CDR1. After treated by RAB, the distribution of green fluorescence was changed, the intensity of fluorescence was decreased compared with the control, and some of them lost the green fluorescence. The downregulation expression level of CDR1 was detected by real-time reverse transcription polymerase chain reaction. Above all, RAB synergize the antifungal effect of azoles against C. albicans by inhibiting efflux pump activity. Cellular ergosterol synthesis was measured using its unique spectrophotetric absorbance profile. Both ergosterol and 24(28)-DHE absorb at 281.5 nm, whereas only 24(28)-DHE absorbs at 230 nm. The decreased cellular ergosterol synthesis was measured using its unique spectrophotetric absorbance profile and we found that when cells were treated with RAB, the expression of ERG11 was downregulated and ergosterol level was decreased. ERG11 expression in C. albicans after treatment by 16μg/ml RAB was markedly lower than untreated isolates (0.42-fold for azole-sensitive strain and 0.23-fold for azole-resistant strain, respectively). Low ergosterol content will enhance the membrane fluidity. An increase in membrane fluidity directly results in increased passive diffusion of drugs and sensitization of Candida cells to antifungals. Transmission electron microscopy investigation found the wrinkled cell membrane and the impaired cell wall due to RAB treatment. RAB synergize the antifungal effect of azoles against C. albicans by inhibiting efflux pump activity, targeting the ergosterol biosynthesis pathway resulted ergosterol depletion, and impairing the function of fungal cell membranes and increasing penetration of an antifungal agent.
About the anticancer activity, the paper studied the activity of steroidal alkaloid glycoside isolated from Chinese herb Solanum Solanum nigrum L. Solamargine (SM), solasonine,β2-solamargine, and solasodine have the same aglycon solanidine, but different saccharide chains. We discussed the structural activity relationships between the steroidal alkaloidal saponins and inhibition of the growth of cancer cells. SM with a two-rhamnosyl on the trisaccharide chain achieved higher intracellular concentrations and was potently toxic. As compared with the tumor cell lines, SM had a lower cytotoxicity on the normal cell retinal pigment epithelial cell line RPE-1 and mesangial cells MC. The cytotoxicity of SM did not correlate with the expression level of the multidrug resistance MDR1 and had the strong cytotoxicity on K562/A02 and KB/VCR. Solasonine, which has a trisacharide chain, has also exhibited moderate cytotoxicity, while other two compounds, without the trisacharide chain, had no anticancer activity. These studies revealed the trisaccharide chain was critical for activity in these steroidal alkaloid saponins. It is likely that apoptosis can be induced by low doses of SM, and oncosis by high doses, both types of cell death are induced by intermediate concentration of SM. Apoptosis was evaluated by DAPI staining and annexin V/PI double staining. Further investigation with human K562 leukemia cells found that SM could induce an early lysosomal rupture within 2h as assessed by acridine-orange relocation and alkalinization of lysosomes. Intracellular lysosomal rupture is also confirmed with the release of cathepsin B to cytosol detected by western blot. Subsequent mitochondrial damage including mitochondrial membrane permeabilization detected by decrease membrane potential as well as the release of cytochrome c from mitochondria was also observed. The down-expression of Bcl-2, up-regulation of Bax, caspase-3 and caspase-9 activities followed by above changes revealed that the cytoxicity of SM was involved in a lysosomal-mitochondrial death pathway induced by SM.
Cell membrane integrity was assessed by detecting the leakage of cytoplasmic content, the release of lactate dehydrogenase (LDH), and the uptake of propidium iodide (PI). The rapid ability of SM (IC80) to make PI permeate into tumor cells, LDH release, and leakage of cytoplasmic content at the same rate (within minutes), suggests a killing mechanism that involves plasma membrane perturbation. We use whole-cell recording to measure the time courses of membrane blebbing and disruption in human K562 leukemia and squamous cell carcinoma KB cells. SM induced membrane blebbing within 5 min of sustained application. Both chelating extracellular calcium with EGTA and clamping intracellular calcium concentrations with a high concentration of the cell-permeable chelator BAPTA-AM did not prevent blebbing. Polyethylene glycols having molecular weights≥3350 blocked membrane blebbing. We also evaluated the effects of PEGs of various molecular weights on antitumor effect of SM. PEG 1000 had no effect on antitumor effect of SM. Chelating extracellular calcium with EGTA did not prevent blebbing after a delay, showing that the formation of blebs does not depend on the influx of calcium. Blebbing was also not affected when the intracellular calcium concentration was clamped by the cell-permeable chelator BAPTA-AM. Blebbing is independent of calcium. SM reduced intracellular ATP levels, disrupted the cytoskeletal systems, and had no effect on cell cycle.
In addition, the quantity drugs associated with intracellular compartments was studied. We used a magnetic capture technique that allows for isolation of lysosomes and sucrose density gradient centrifugation for isolation of mitochondrial. After incubation with SM, cells were separated into fractions containing cytosol, lysosomes, and mitochondria and quantitation of compounds by LC/MS/MS. It is reported that receptor-mediated endocytosis cause lysosomal alkalinization and swollen. The amounts of SM that accumulated in the lysosomes and mitochondrial were determined. SM was found to preferentially accumulate within lysosomes in drug-resistant cells. These results suggest the internalization of SM in cancer cells may be related to rhamnose receptor-mediated endocytosis through endosomes, leading to localization in the lysosomes. In addition, the lumenal PH of lysosomes is known to be considerably lower in MDR cells, resulting in an enhanced lysosome-to-cytosol pH differential. SM, as a weakly basic compound, may become ionized and unable to diffuse back through the lipid monolayer of lysosomal membrane.
In this thesis, we described the antifungal activity of RAB and its capacity to reverse azole resistance. It can be used clinically as an antifungal agent to potentiate azole antifungal agents. About the anticancer activity, it's the first report SM (IC80) can induce oncosis on cancer cell. Apoptosis is the process of programmed cell death and has little effect upon surrounding tissue. However, oncosis resulting from cell membrane damage and the leakage of contents can cause inflammation of surrounding tissue. Rational use of anticancer agents will reduce the dose toxicity and achieve a better anticancer effect. The intracellular distribution of SM was also studied in this paper. SM was found to preferentially accumulate within lysosomes in drug-resistant cells, which is important to drug delivery and its target research
引文
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