抗肿瘤药物与miRNA靶点相互作用研究进展

miRNA是一大类非编码的小分子RNA,在肿瘤等许多疾病的发生过程中起重要作用。该文综述了miRNA的生物合成过程以及有关的酶与辅助因子,抗肿瘤药物对miRNA表达的改变以及药物与miRNA靶点的相互作用和机制。同时提出了有关miRNA的功能研究,以miRNA为靶点的药物筛选以及药物对miRNA表达的调控机制是未来研究的重点。     

抗肿瘤反义寡核苷酸药物靶标的研究进展

肿瘤是一种多基因相关疾病，反义寡核苷酸药物可以特异性地与靶基因mRNA互补结合，封闭靶基因的表达，在肿瘤的基因治疗中独树一帜。现已发现许多基因在调节细胞增殖和衰老、细胞凋亡、细胞周期、血管生成及信号转导等方面起着重要作用，并证实它们在抗肿瘤反义治疗中可以作为有效的分子靶标。本文综述了近年来发现的抗肿瘤反义寡核苷酸的治疗靶点，并提出了多靶点反义寡核苷酸联合应用治疗肿瘤的新观念。     

基于数据库的大黄素协同化疗药物抗肿瘤机制探讨

目的 通过药物靶点数据库对大黄素分子机制进行模拟探讨,为研究大黄素协同抗肿瘤化疗药物提供新的研究策略.方法 借助在线数据库资源收集大黄素已知靶点,通过文献及靶点功能数据库筛选具有协同肿瘤化疗药物的潜在靶点,根据靶点构建蛋白-蛋白相互作用(PPI)网络,对潜在靶点KEGG通路分析,明确其发挥协同作用分子机制.结果 大黄素...     

喹唑啉结构的多靶点酪氨酸激酶抑制剂研究进展

随着肿瘤机制和抗肿瘤药物的深入认识,多靶点酪鼠酸激酶抑制剂的抗肿瘤作用是临床研究的主要方向,本文对含喹唑啉结构的酪氨酸激酶抑制剂的研究进展作一综述。     

P-糖蛋白与多药耐药的关系

肿瘤多药耐药(M ultidrug R esistance,M D R)是指一种药物作用于肿瘤使之产生耐药性后,该肿瘤对未接触过的、结构无关、机制各异的多种抗肿瘤药也具有交叉耐药性的现象。耐药的产生取决于作用靶点部位的药物浓度、靶点本身的量和质以及靶点和药物之间的相互作用,而M D R产生的机制比较复杂,涉及到药物的外排增加和亚细胞分布改变;药物作用靶标如拓扑异构酶改变;代谢转化改变;损伤修复增强;凋亡相关通路改变;细胞增殖速率变化;体内药代动力学因素等。这些机制常可同时存在,但以一种为主,且不同机制间常相互影响。本文就近年来M D R产生…     

基于HDAC的双靶点抗肿瘤药物研究进展

多靶点作用的抗肿瘤药物比目前单靶点药物具有更好的药效,且能够降低耐药性和毒副作用。为了探索多靶点药物在肿瘤化疗中的应用前景,以组蛋白去乙酰化酶(HDAC)抑制剂为基础设计多种作用的双靶点抑制剂已经成为了研究热点,其中部分化合物抑制肿瘤细胞增殖活性比现有的上市药物更好。本文综述了基于HDAC的双靶点抑制剂的研究进展,重点介绍了作用机制、设计策略和生物活性。     

以细胞骨架为靶点的海洋抗肿瘤大环内酯类化合物的研究进展

海洋生物是抗肿瘤活性物质的重要来源,不同的活性物质因其结构不同而具备不同的生物活性。大环内酯是其中的重要部分,其作用机制主要与结构中的内酯环相关。大多数海洋大环内酯类化合物通过作用于细胞骨架发挥其抗肿瘤活性。细胞骨架包括微丝、微管和中间纤维,微丝和微管分别由肌动蛋白和微管蛋白聚合而成,药物正是通过改变它们的解聚、聚合作用而发挥其抗肿瘤作用。细胞骨架在功能上与细胞结构、胞内运输和细胞分裂密切相关,已成为肿瘤化疗中的新靶点。现综述以细胞骨架为靶点的具有抗肿瘤活性的海洋大环内酯类化合物,以及其作用机制、生物活性的研究进展。     

作用于多靶点的组蛋白去乙酰化酶抑制剂结构设计的研究进展

目的 肿瘤产生机制的复杂性,要求对多种促肿瘤发生发展机制同时抑制,才能有效阻止肿瘤生长。组蛋白去乙酰化酶抑制剂(HDACi)作为一种新型抗肿瘤药物,能诱导肿瘤细胞凋亡, 阻止癌细胞增长。利用结构的多样性和变通性设计新颖的作用于多靶点的HDACi。方法 分类总结大量已被报道的多靶点组蛋白去乙酰化酶抑制剂。结果 多靶点抑制剂在临床实验中表现出了较好的抗肿瘤活性。结论 多靶点单一分子的HDACi的研究日益引起人们的重视,具有广阔的研发前景。     

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。     

靶向和多靶抗肿瘤策略

肿瘤药物研究的临床成功率为心血管疾病药物的1／3。肿瘤仍然具有分布广泛和致命性的特征。尽管研究机构很多，但治疗结果方面，疾病的总体改善率仍然不令人满意。抗肿瘤策略研究即显得尤为重要。对于抗癌药物靶点，必须区别必要靶点和非必要的靶点。针对于必要靶点，特异性抑制剂可能具有较窄的治疗窗。而靶向于非必要靶蛋白质，则可能具有较好的耐受性．但其作用可能较弱。     

RP-HPLC和UV-VIS法测定灵芝不同收获期的多糖肽和灵芝酸

目的研究灵芝不同栽培方式和不同收获期中多糖肽和灵芝酸A、B的变化,为灵芝规范化栽培及制定产品质量标准提供依据。方法 RP-HPLC测定菌草灵芝和仿野生栽培的灵芝提取物的灵芝酸A、B的变化。色谱柱为XB-C18柱(150mm×4.6mm,5μm),流动相为0.05%磷酸-乙腈(65:35),检测波长254nm,常温,进样量50μL。以灵芝多糖肽为对照品,采用Folin-酚试剂法,通过紫外-可见吸收光谱法检测菌草灵芝和仿野生栽培灵芝不同收获期提取物的多糖肽。结果灵芝酸A、B线性范围分别为14.8～371.0和16.4～409.0μg/mL,平均回收率为95.0%、100.5%,RSD分别为1.18%、3.37%(n=6)。灵芝多糖肽在100～600μg/mL与吸光度值呈线性关系,r=0.9995,回收率95%～100%。结论该方法简便、快速,可用于灵芝及其产品中多糖肽和灵芝酸A、B的质量控制。菌草灵芝沸水提取能将多糖肽和灵芝酸分离,既简化了灵芝水、醇提取工艺,又提高经济效益。     

大鼠灌胃灵芝总三萜后血浆中灵芝酸类成分的检测

研究灵芝中总三萜在大鼠体内的吸收情况。大鼠灌胃给予灵芝总三萜后,利用HPLC-DAD和LC-MS方法鉴定大鼠血浆中的灵芝酸类成分。在大鼠血浆中检测到5种灵芝酸类成分,即灵芝酸C2、灵芝酸C6、灵芝酸G、灵芝酸B和灵芝酸A。大鼠口服灵芝总三萜后灵芝中的灵芝酸类成分能被大鼠吸收。     

Sensitive and selective liquid chromatography-tandem mass spectrometry method for the determination of five ganoderic acids in Ganoderma lucidum and its related species

The present paper describes a novel, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous analysis of ganoderic acids C(2), B, A, H, D in Ganoderma lucidum and its related species. Ganoderma samples were prepared using simple ultrasonic extraction. Chromatographic separation was carried out on an Agilent Zorbax XDB C(18) column (250 mm × 4.6 mm i.d., 5μm) with an isocratic mobile phase consisting of acetonitrile, water and formic acid (42:58:0.5, v/v/v). Mass spectrometric detection was achieved by a triple-quadrupole mass spectrometer equipped with an atmospheric pressure chemical ionization (APCI) interface operating in negative and positive ionization mode via a single within-run polarity switching. Quantitation of five ganoderic acids was performed using selective reaction monitoring (SRM) mode. The intra- and inter-day precision was less than 6.2% and the accuracy ranged from 90.0% to 105.7%. The limit of quantification (LOQ) was 20.0-40.0 ng/mL and the limit of detection (LOD) was 3.0-25.0 ng/mL. With this method, low levels of ganoderic acids in the fruiting bodies of Ganoderma sinense and Ganoderma applanatum were accurately quantified for the first time. Importantly, the method allows unequivocal quantification of the five ganoderic acids in the spores and fruiting bodies of Ganoderma lucidum, whereas the previously published methods have lacked the capability. The method presented will be a powerful tool for quality control of Ganoderma lucidum and its related species.     

Multidrug resistance-associated proteins and implications in drug development

1.  The multidrug resistance-associated proteins (MRPs) belong to the ATP-binding cassette superfamily (ABCC family) of transporters that are expressed differentially in the liver, kidney, intestine and blood–brain barrier. There are nine human MRPs that transport a structurally diverse array of endo- and xenobiotics as well as their conjugates.
2.  Multidrug resistance-associated protein 1 can be distinguished from MRP2 and MRP3 by its higher affinity for leukotriene C₄. Unlike MRP1, MRP2 functions in the extrusion of endogenous organic anions, such as bilirubin glucuronide and certain anticancer agents. In addition to the transport of glutathione and glucuronate conjugates, MRP3 has the additional capability of mediating the transport of monoanionic bile acids.
3.  Both MRP4 and MRP5 are able to mediate the transport of cyclic nucleotides and confer resistance to certain antiviral and anticancer nucleotide analogues. Hereditary deficiency of MRP6 results in pseudoxanthoma elasticum. In the body, MRP6 is involved in the transport of glutathione conjugates and the cyclic pentapeptide BQ123.
4.  Various MRPs show considerable differences in tissue distribution, substrate specificity and proposed physiological function. These proteins play a role in drug disposition and excretion and thus are implicated in drug toxicity and drug interactions. Increased efflux of natural product anticancer drugs and other anticancer agents mediated by MRPs from cancer cells is associated with tumour resistance.
5.  A better understanding of the function and regulating mechanisms of MRPs could help minimize and avoid drug toxicity and unfavourable drug–drug interactions, as well as help overcome drug resistance.     

Discovery of N-pyridoyl-Δ2-pyrazolines as Hsp90 inhibitors

Hsp90, as a key molecular chaperone, plays an important role in modulating the activity of many cell signaling proteins and is an attractive target for anticancer therapeutics. Herein, we report the discovery of N-pyridoyl-Δ²-pyrazoline analogs as novel Hsp90 inhibitors by integrated approaches of drug design, organic synthesis, cell biology, and qualitative proteomic analysis. Novel chemical compounds were designed and optimized in the adenosine triphosphate-binding site of Hsp90; lead optimized compounds were found to have significant interactions with Asp93 and other amino acids crucial for Hsp90 inhibition. The designed compounds were synthesized by a two-step procedure; different aromatic aldehydes were reacted with various acetophenones to form substituted 1,3-diphenyl-prop-2-enones ( Ic–Io ), which upon reaction with isonicotinic acid hydrazide in the presence of glacial acetic acid form N-pyridoyl-Δ²-pyrazoline compounds ( PY1–PY13 ). Compounds PY3 , PY2 , and PY1 were identified as potential leads amongst the series, with promising anticancer activity against human breast cancer and melanoma cells, and the ability to inhibit Hsp90 similar to radicicol by drug-affinity responsive target stability proteomic analysis in a whole-cell assay.     

Antimicrobial properties, antioxidant activity and cytotoxicity of ethanol-soluble acidic components from Ganoderma atrum

The aim of this study was to investigate the possibility of ethanol-soluble acidic components (ESAC) from Ganoderma atrum as a novel source against bacteria and oxidation in food industry. The qualitative analysis of ESAC was based on liquid chromatography-mass spectrometry (LC/MS) and eight ganoderic acids were identified in ESAC. Its total phenolic content of ESAC was 75.80±5.67 mg/g. ESAC exhibited antimicrobial activity against all of the tested bacteria (Staphylococcus aureus subsp. Aureus, Escherichia coli, Bacillus subtilis and Proteusbacillus vulgaris), and exerted antioxidant activities by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, total reducing power and β-carotene bleaching assays. Moreover, ESAC (at concentrations of 0-100 μg/mL) did not show any cytotoxic effects in RAW264.7 murine macrophage cells. Our findings suggested that ESAC has the potential as a novel natural source for food industry, ganoderic acids and phenolic compounds may be related to its antimicrobial properties as well as antioxidant activities.     

Cytotoxic and pro-apoptotic effects of novel ganoderic acid derivatives on human cervical cancer cells in vitro

Ganoderic acid T, a triterpenic acid produced by Ganoderma lucidum, has demonstrated therapeutic potential for tumor disease. In the current work, ganoderic acid T was modified to produce more effective small-molecule inhibitors of cancer cell proliferation. Moreover, the anticancer effects of three new ganoderic acid T derivatives, i.e., (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid ethyl ester (TLTO-Ee), (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid propyl ester (TLTO-Pe), and (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid amide (TLTO-A), and one known derivative, (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid methyl ester (TLTO-Me), on the cervical cell line HeLa were investigated and compared. MTT assay indicated that, among the tested compounds, TLTO-A displayed the highest inhibitory effect on the growth of HeLa cells, whereas it showed less cytotoxicity to the non-tumorous cell line MCF-10A than ganoderic acid T. Flow cytometry analysis revealed that all the compounds caused cell cycle arrest at the G1 phase and induced apoptosis. Furthermore, they decreased the mitochondrial membrane potential and enhanced the activities of pro-apoptotic factors caspase-3 and caspase-9 in a dose-dependent manner. Accordingly, the apoptosis induction was presumed to occur through the endogenous pathway. The following order ranks both cytotoxic and pro-apoptotic effects of the compounds against HeLa cells: TLTO-A>ganoderic acid T≈TLTO-Me≈TLTO-Ee≈TLTO-Pe. This study suggests that the carboxyl group of ganoderic acid T is not the main active group and is suitable for its further structural modification. The current work presents valuable information on the design of ganoderic acid T derivatives to develop potential chemotherapy agents.     

星点设计-效应面法优化鹿角灵芝微乳超声提取工艺

目的 探讨以微乳超声法同时提取鹿角灵芝中灵芝酸和灵芝多糖的最佳条件。方法 采用星点设计-效应面法,以物料溶剂比(X₁)、超声提取时间(X₂)和超声功率(X₃)作为考察因素,以灵芝酸A、灵芝酸C₂、灵芝多糖含量和提取物得率为考察指标,并对考察因素和考察指标总评归一值进行多元线性回归和二项式拟合,以效应面优选最佳的微乳超声提取工艺,并做验证试验。结果 微乳超声提取鹿角灵芝的最佳条件为物料溶剂比1∶18、超声提取时间59 min、超声功率513 W,此条件下灵芝酸A、灵芝酸C₂、灵芝多糖含量和提取物得率分别为0.647 8,0.108 5,11.20 mg·g^-1和34.28%。结论 微乳超声可同时提取鹿角灵芝中脂溶性和水溶性成分,并且节能、省时、操作简便,为工业化提取鹿角灵芝提供了新途径。     

Coumarin derivatives with anticancer activities: An update

Cancer can invade or spread to almost all parts of the body. The increasing morbidity and high mortality of cancer create a great demand for the development of novel anticancer drugs. Coumarin derivatives are ubiquitous in nature and can readily interact with diverse enzymes and receptors in cancer cells via weak bond interactions; hence, coumarin is a highly privileged pharmacophore for the development of novel anticancer agents. This review will focus on the recent development of coumarin hybrids as potential anticancer agents covering articles published from 2019 to 2020.