壳聚糖抗肿瘤作用的研究进展

壳聚糖及其衍生物具有抗肿瘤的作用,其抗肿瘤机制既可直接作用于肿瘤细胞,干扰细胞代谢,抑制细胞生长,诱导细胞凋亡,又可通过增强机体免疫功能,发挥抗肿瘤作用。此文对壳聚糖及其衍生物的抗肿瘤作用进行了综述     

隐丹参酮及其衍生物抗肿瘤活性研究进展

隐丹参酮是中药丹参的有效成分之一,对多种肿瘤显示很好的活性。其抗肿瘤效应包括抑制细胞增殖、诱导肿瘤细胞凋亡、抑制细胞迁移和侵袭、调节机体免疫功能和逆转药物耐药性等。抗肿瘤直接靶点有信号转导和转录激活因子3(STAT3)、酪氨酸蛋白磷酸酶SHP2、DNA拓扑异构酶2(top2),其它的作用机制包括诱导活性氧（ROS）产生、调控雌、雄激素受体信号、抑制PI3K/AKT信号通路等。此外,近年来研究人员还设计合成了许多隐丹参酮衍生物,并对其抗肿瘤作用进行了研究。本文主要就隐丹参酮及其衍生物抗肿瘤活性研究进展进行综述,希望能够有助于隐丹参酮及其衍生物在抗肿瘤方面的药物研发。     

虫草素抗肿瘤作用分子机制研究进展

虫草素是一种脱氧核苷类似物,具有抗肿瘤、抗白血病、抗菌、抗衰老、免疫调节和清除体内自由基等多种药理作用,对多种疾病尤其是恶性肿瘤具有明确的治疗作用。虫草素抗肿瘤作用机制及其靶点目前已成为分子生物学研究的新热点。虫草素在细胞内有多个作用靶标,可调控肿瘤细胞生长、增殖和转移等过程。虫草素发挥抗肿瘤的作用机制包括抑制嘌呤、DNA和RNA合成及蛋白质翻译,诱导肿瘤细胞凋亡和调控细胞周期,抗肿瘤细胞侵袭,抑制血小板凝集和抗炎5个途径及其相应的信号通路。虫草素在体内迅速脱氨从而丧失生物活性。笔者提出了合成虫草素衍生物、虫草素与腺苷脱氨酶抑制剂联合用药及与纳米新材料等形成新的复合物等3个解决方案,旨在为虫草素的研发提供新的思路,为其临床应用奠定理论基础。     

紫草素的抗癌作用机制研究进展

紫草素是传统中药紫草中一种重要的活性成分。该研究从紫草素抑制细胞增殖和迁移，诱导细胞自噬、凋亡、坏死和细胞免疫等 5个方面，综述了其对白血病、肺癌、肝癌、乳腺癌、胰腺癌和宫颈癌等多种肿瘤的抗癌作用最新研究进展，这些机制主要包括:触发活性氧产生，诱导细胞周期阻滞、线粒体功能障碍和自噬，减少外泌体释放，激活抗肿瘤免疫，调节微小 RNA(microRNA，miRNA/miR)、促分裂原活化的蛋白激酶( MAPKs)等癌症相关信号通路以及转录因子表达，抑制糖代谢途径等。并进一步总结发现紫草素衍生物经过萘醌环或侧链修饰后，具有比紫草素更强的抗癌活性和更低的毒性等令人耳目一新的应用进展，该综述可以为紫草素及其衍生物抗癌作用机制的深入研究和临床开发利用提供依据。     

紫草素及其衍生物的药理作用研究进展

［摘要］紫草素及其衍生物提取自传统中药紫草。实验研究显示,紫草素及其衍生物具有抗炎、抗氧化、抗病毒、抗肿瘤等多种药理活性,对多种肿瘤细胞都有确切的抑制生长及促凋亡的作用。对心血管系统有保护作用 。在紫草素及其衍生物的众多药理活性中,其抗炎及抗肿瘤活性表现突出,是目前研究的热点和重点,有望成为治疗这类重大疾病的新药。     

青蒿素及其衍生物抗肿瘤分子机制的研究进展

目的:为青蒿素类抗肿瘤药物的开发提供参考。方法:通过Pub Med、中国知网检索2002-2014年国内外有关青蒿素及其衍生物抗肿瘤研究文献,进行系统归纳、总结和综述。结果与结论:青蒿素及其衍生物通过对细胞周期的阻滞抑制肿瘤细胞的增殖;通过作用于Bcl-2家族和Caspase家族诱导细胞的凋亡;通过调控基质金属蛋白酶和整合蛋白的表达抑制肿瘤细胞的侵袭及转移;通过调控与血管形成相关的基因如血管内皮生长因子等抑制肿瘤血管形成。深入研究青蒿素及其衍生物的分子机制,对于寻找抗肿瘤药物新的作用靶点和开发相关新药具有重要意义。     

紫草素药理作用研究进展

紫草素是从传统中药紫草中提取的一类萘醌类化合物,具有多种生物学活性,特别是良好的抗肿瘤作用已被大量研究所证实。文章在文献报道的基础上,对紫草素的相关药理作用及其研究进展进行了综述,重点阐述紫草素的抗炎、抗病毒、抗脂肪生成、抗雌激素、抗肿瘤、免疫调节等方面的药理作用。最后对紫草素的研究现状进行概述,并对以紫草素为先导的临床药物研究加以展望。     

紫草素诱导HeLa细胞凋亡经过caspase激活的机制

目的　研究紫草素诱导HeLa细胞凋亡的作用机制。方法　MTT法测定紫草素对HeLa细胞的生长抑制实验 ,荧光染色等观察细胞形态学变化 ;DNA电泳、LDH法研究细胞死亡的途径。免疫印迹实验检测相关蛋白的表达。结果　紫草素具有明显的抑制HeLa细胞生长的作用 ,并呈明显的量效关系和时间依赖性 ,4 0 μmol·L- 1 的紫草素在 2 4h内可诱导细胞凋亡 ,凋亡途经与死亡受体信号途径相似 ,经历了半胱氨酸天冬氨酸蛋白酶 3和 8(caspase 3和caspase 8)的激活。结论　 4 0 μmol·L- 1 的紫草素可明显地诱导HeLa细胞凋亡 ,其信号转导途径为经典的caspase途径     

抗肿瘤活性的肝素衍生物研究进展

在应用肝素及低分子量肝素(LMWH)防治肿瘤患者血栓栓塞性并发症时发现它们还具有显著的抗肿瘤活性,但其强大的抗凝活性成为抗肿瘤药物应用时的制约因素。对肝素进行化学修饰或将其与其他化合物偶联可获得抗凝活性低、抗肿瘤活性高的肝素衍生物。肝素衍生物的抗肿瘤机制有抑制类肝素酶活性、抑制P、L选择素介导的细胞间相互作用及抑制血管生长因子活性等。类肝素酶降解硫酸乙酰肝素(HS)侧链与肿瘤转移及肿瘤血管生成密切相关,P、L选择素介导的细胞间相互作用对肿瘤细胞的血源性转移过程有重要作用,血管生长因子所触发的血管生成是肿瘤生长、转移的必要条件。不同结构的肝素衍生物其抗肿瘤机制不完全相同。文章对抗肿瘤活性肝素衍生物的结构及其抗肿瘤机制作了综述。     

天然生物碱及衍生物抗肿瘤机制研究进展

生物碱是存在于中草药中的主要抗肿瘤活性成分之一,近年来天然生物碱及衍生物的抗肿瘤机制研究取得了较大进展。特别是在缺氧诱导因子-1、端粒酶、拓扑异构酶等作用靶点上取得的新进展,该文主要就这3个靶点进行综述。     

Shikonin and its derivatives: a patent review

Introduction: Shikonin and its derivatives are the main components of red pigment extracts from Lithospermum erythrorhizon, whose medicinal properties have been confirmed for a long history, and have aroused great interest as the hallmark molecules responsible for their significant biological activities, especially for their striking anticancer effects. Areas covered: Areas covered in this paper include a review of the total synthesis, biological effects and mechanisms of shikonin and its derivatives for their anticancer activities in the past decade, basing on literature and patents. The current state and problems are also discussed. Expert opinion: At present, screening for anticancer shikonin derivatives is based on cellular level to find compounds with stronger cytotoxicity. Though several compounds have been discovered with striking cytotoxicity in vitro, however, no selectivity was observed and undoubtedly, the further outcomes have been disappointing because of their great damage to normal cells. Meanwhile, the presumed mechanisms of action are also established in terms of their cytotoxicity. From a pharmacological point of view, most of the shikonin derivatives are at an early stage of their development, and thus it is difficult to determine the exact effectiveness in cancer treatment. With research in this field going deeper, it can be expected that, despite the difficulties, shikonin derivatives as potential anticancer agents will soon follow.     

Shikonin and its derivatives: a patent review

Introduction: Shikonin and its derivatives are the main components of red pigment extracts from Lithospermum erythrorhizon, whose medicinal properties have been confirmed for a long history, and have aroused great interest as the hallmark molecules responsible for their significant biological activities, especially for their striking anticancer effects.

Areas covered: Areas covered in this paper include a review of the total synthesis, biological effects and mechanisms of shikonin and its derivatives for their anticancer activities in the past decade, basing on literature and patents. The current state and problems are also discussed.

Expert opinion: At present, screening for anticancer shikonin derivatives is based on cellular level to find compounds with stronger cytotoxicity. Though several compounds have been discovered with striking cytotoxicity in vitro, however, no selectivity was observed and undoubtedly, the further outcomes have been disappointing because of their great damage to normal cells. Meanwhile, the presumed mechanisms of action are also established in terms of their cytotoxicity. From a pharmacological point of view, most of the shikonin derivatives are at an early stage of their development, and thus it is difficult to determine the exact effectiveness in cancer treatment. With research in this field going deeper, it can be expected that, despite the difficulties, shikonin derivatives as potential anticancer agents will soon follow.     

Impairment of vascular function of rat thoracic aorta in an endothelium-dependent manner by shikonin/alkannin and derivatives isolated from roots of Macrotomia euchroma

The effects of a naphthoquinone analogue, shikonin/alkannin (SA) and derivatives (acetylshikonin and beta,beta-dimethylacrylshikonin), on vascular reactivity were studied with isolated rat aortic rings. At lower concentrations, SA and its derivatives concentration-dependently inhibit the agonist-induced (acetylcholine and histamine) relaxation in PE precontracted aorta in an endothelium-dependent manner with IC (50) values ranging from 0.2 to 1.5 microM. In addition to the effect on agonist-induced vasorelaxation, the Ca (2+) ionophore A23187-induced vasorelaxation was also inhibited or reversed by SA. However, SA had no effect on sodium nitroprusside-induced (guanylate cyclase activator) vasorelaxation. These data suggested that SA and its derivatives might be acting as inhibitors of nitric oxide synthesis in endothelium. At a concentration greater than 10 microM, SA induced contraction of intact but not denuded aorta which could be inhibited by prior treatment with indomethacin, a cyclooxygenase inhibitor. In summary, the results from this study showed that SA and its derivatives inhibited agonist-induced relaxation at lower concentrations and induced vasocontraction at higher concentrations. All the effects seen with SA were endothelium-dependent, however, through different mechanisms. Abbreviations. SA:shikonin/alkannin PE:phenylephrine Ach:acetylcholine SNP:sodium nitroprusside eNOS:endothelial nitric oxide synthase L-NAME: Nw-nitro- L-arginine methyl ester     

Shikonin, acetylshikonin, and isobutyroylshikonin inhibit VEGF-induced angiogenesis and suppress tumor growth in lewis lung carcinoma-bearing mice

Lithospermum erythrorhizon has been used for treatment of inflammatory diseases and cancer as a folk remedy. Based on the evidences that anti-inflammatory agents frequently exert antiangiogenic activity, thus we examined comparatively the antiangiogenic activities of three naphthoquinone derivatives (shikonin, acetylshikonin, and isobutyroylshikonin) isolated from the plant. Three derivatives exhibited weak cytotoxicity against human umbilical vein endothelial cells (HUVECs) with IC50 of over 20 microM. Shikonin had more specific inhibitory effects on proliferation and vascular endothelial growth factor (VEGF) production by VEGF compared with different derivatives. All of derivatives significantly suppressed the migration of VEGF treated HUVECs at different optimal concentrations. Also, shikonin and acetylshikonin significantly disrupted VEGF-induced tube formation. Furthermore, three derivatives effectively downregulated the expression of urokinase-type plasminogen activator (uPA), but not its receptor uPAR. Additionally, shikonin significantly inhibited tumor growth in LLC-bearing mice, whereas its derivatives had relatively mild effects. Taken together, our findings suggest that shikonin and its derivatives exhibit the antiangiogenic and antitumorigenic effects by suppressing proliferation and angiogenic factors.     

Shikonin Directly Inhibits Nitric Oxide Synthases: Possible Targets That Affect Thoracic Aorta Relaxation Response and Nitric Oxide Release From RAW 264.7 Macrophages

Recently, an isomeric mixture of herbal anti-inflammatory naphthoquinones shikonin and alkannin, and their derivatives, have been found to impair cellular responses involving nitric oxide (NO) and NO synthesis, like the acetylcholine-induced relaxation response of rat thoracic aorta and NO release from murine RAW 264.7 macrophages. However, the mechanisms of such effects, including whether NO synthase (NOS) activity is affected, remained unclear. We herein investigate possible targets of shikonin in these NOS-related events. Shikonin by itself dose-dependently inhibited the rat thoracic aorta relaxation in response to acetylcholine (pD′₂ value: 6.29). Its optical enantiomer, alkannin, was equally inhibitory in the aorta relaxation–response assay. In RAW 264.7 cells, shikonin inhibited the lipopolysaccharide-induced NO production by 82% at 1 μM. A cell-free assay to verify direct effects on NOS activity showed that shikonin inhibits all isoforms of NOS (IC₅₀ s, 4–7 μM), suggesting NOS as an inhibition target in both the events. Further possible targets of shikonin that might be involved in the inhibitions of the acetylcholine-induced aorta relaxation response and the NO generation by RAW 264.7 cells are also discussed. It is shown for the first time that shikonin inhibits NOS activity.     

紫草宁生物合成相关的代谢酶及基因

紫草是一种重要的中草药材，其培养细胞在M9培养基中可以大量生产主要的药物成分紫草宁。本文主要论述了在紫草细胞中与紫草宁形成相关的代谢酶和基因方面取得的研究进展，分别讨论了这些代谢酶和基因克隆的功能及表达特性，对植物次生代谢、紫草宁次生药物的生产调控及其代谢工程等研究具有重要的意义。     

Shikonin suppresses IL-17-induced VEGF expression via blockage of JAK2/STAT3 pathway

IL-17 signaling in keratinocytes plays an important role in psoriasis, which is a benign, chronic skin disease characterized by keratinocytes hyperproliferation and increased dermal vascularity. Shikonin, isolated from the traditional medical herbs Lithospermum erythrorhizon, has long been found to possess different medicinal properties such as antibacterial, improving wound healing, anti-inflammatory and anti-tumor effects. However, the effects and mechanisms of shikonin on VEGF expression in keratinocytes mediated by IL-17 signaling, are still not fully clarified. In the present study, we investigated the effects and regulatory mechanisms of shikonin on VEGF expression in keratinocytes induced by IL-17 by in vitro and in vivo experiments. Our results showed that shikonin significantly inhibited IL-17-induced VEGF mRNA and protein expression in HaCaT cells and the secretion of VEGF by HaCaT cells, inhibited IL-17-induced IL-17R, pJAK2 and pSTAT3 expression, while up-regulated the expression of SOCS1 in HaCaT cells. Additionally, shikonin effectively suppressed VEGF expression in the skin of IL-17 stimulated mice. Furthermore, shikonin suppressed VEGF-induced tube formation of HUVECs and CD34 expression in the skin of IL-17 stimulated mice. These results imply that shikonin suppresses IL-17-induced VEGF expression in vitro and in vivo and the mechanisms may be related to its effect in blockage of JAK2/STAT3 pathway. These data deepen our understanding of shikonin in the inhibition of angiogenesis in inflammatory skin diseases such as psoriasis.     

Gallic acid and gallic acid derivatives: effects on drug metabolizing enzymes

Gallic acid and its structurally related compounds are found widely distributed in fruits and plants. Gallic acid, and its catechin derivatives are also present as one of the main phenolic components of both black and green tea. Esters of gallic acid have a diverse range of industrial uses, as antioxidants in food, in cosmetics and in the pharmaceutical industry. In addition, gallic acid is employed as a source material for inks, paints and colour developers. Studies utilising these compounds have found them to possess many potential therapeutic properties including anti-cancer and antimicrobial properties. In this review, studies of the effects of gallic acid, its esters, and gallic acid catechin derivatives on Phase I and Phase II enzymes are examined. Many published reports of the effects of the in vitro effects of gallic acid and its derivatives on drug metabolising enzymes concern effects directly on substrate (generally drug or mutagen) metabolism or indirectly through observed effects in Ames tests. In the case of the Ames test an antimutagenic effect may be observed through inhibition of CYP activation of indirectly acting mutagens and/or by scavenging of metabolically generated mutagenic electrophiles. There has been considerable interest in the in vivo effects of the gallate esters because of their incorporation into foodstuffs as antioxidants and in the catechin gallates with their potential role as chemoprotective agents. Principally an induction of Phase II enzymes has been observed however more recent studies using HepG2 cells and primary cultures of human hepatocytes provide evidence for the overall complexity of actions of individual components versus complex mixtures, such as those in food. Further systematic studies of mechanisms of induction and inhibition of drug metabolising enzymes by this group of compounds are warranted in the light of their distribution and consequent ingestion, current uses and suggested therapeutic potential. However, it must be noted that numerous constituents of foodstuffs have been found to be potent modulators of xenobiotic metabolism and the net human health effects may depend on concentrations of individual components and individual genetic makeup.