双氢青蒿素诱导肿瘤细胞凋亡的信号通路研究进展

双氢青蒿素作为青蒿素的重要衍生物,是我国自行研制出的抗疟新药。近些年来,人们对双氢青蒿素进行了多方面的研究,在抗肿瘤研究方面有许多新进展,发现其诱导肿瘤细胞凋亡的机制与多条信号通路有关,例如PI3K/Akt、MAPK、STAT3、Wnt/β-catenin、NF-κB等信号通路。通过对作用机制的深入研究和阐述有望发现双氢青蒿素的新适应症,使其在临床上的应用更加广泛。     

双氢青蒿素对人肺腺癌A549细胞的体外抑制作用研究

目的 观察双氢青蒿素对肺腺癌A549细胞的体外抑瘤效应，并对其抗癌机理作出初步探索。方法 双氢青蒿素对体外培养肺腺癌A549细胞的生长抑制作用采用MTT检测法，细胞凋亡率检测用流式细胞术，并用荧光显微镜及透射电镜观察凋亡细胞的形态学特征。结果 双氢青蒿素半数抑瘤浓度为230nM，双氢青蒿素作用后细胞出现凋亡形态改变，流式细胞术结果出现凋亡峰。结论 双氢青蒿素有较明显抑瘤效应，其抗癌机理可能与诱导细胞凋亡有关。     

CIK细胞辅助治疗卵巢癌的临床疗效

目的 观察杀伤细胞(CIK细胞)辅助治疗卵巢癌的临床疗效及治疗中的不良反应.方法 体外培养的CIK细胞通过静脉输注对19例卵巢癌患者化疗后进行治疗,将治疗前后的结果进行比较.结果 治疗有效率为21.5%;16例(84.4%)患者血清CA-125下降,6例(31.6%)降到正常值;12例(63.2%)生命质量明显改善.治疗的主要不良反应是发热,病人体温37.5～38.5℃,发热持续2h自行缓解.结论 CIK细胞治疗卵巢癌是一种安全、有效的方法.     

双氢青蒿素对卵巢癌细胞株HO-8910生长及Ang-2表达的影响

目的观察双氢青蒿素对人卵巢癌细胞HO-8910裸鼠移植瘤生长及Ang-2表达的影响。方法建立人卵巢癌细胞株系HO-8910裸鼠皮下移植瘤模型。实验分为空白组、顺铂组、青蒿素高剂量组、青蒿素低剂量组、青蒿素高剂量+顺铂组(各组n=5),观测各组小鼠成瘤情况,肿瘤重量差异以及常规病理检查变化,并采用免疫组化法检测肿瘤组织内Ang-2表达情况。结果与给药组比较,对照组小鼠体重大、生长快(P<0.05)。与青蒿素低剂量组比较,高剂量组、顺铂组和联合组肿瘤生长较慢,重量减轻,其抑瘤率分别为49.24%,56.06%,75.00%,差异有统计学意义(P<0.01)。其中联合用药组效果最好(P<0.05),而高剂量组和顺铂组差异无统计学意义(P>0.05)。免疫组化结果提示给药组中Ang-2的含量明显低于对照组(P<0.05),高剂量组比低剂量组更少(P<0.05),而联合处理组几乎未见Ang-2的表达。结论双氢青蒿素对人卵巢癌裸鼠皮下移植瘤的生长具有抑制作用且成剂量依赖性,与化疗药联合应用效果更好,其机制可能是青蒿素下调Ang-2的表达,直接或间接影响肿瘤组织血管生成而发挥抗肿瘤作用。     

肿瘤新生血管生成抑制剂的研究进展

绝大多数恶性实体肿瘤如卵巢癌、肝癌、宫颈癌和乳腺癌都是血管依赖性肿瘤。在恶性肿瘤的生长和转移过程中,肿瘤新生血管生成起着非常重要的作用。当肿瘤生长超过1．0-2．0mm^3时就需要新生血管支持,它为肿瘤的生长和转移提供了所必需的营养和氧气。破坏或抑制肿瘤的新生血管生成,能有效阻止肿瘤血管网的形成从而抑制肿瘤的发展。     

双氢青蒿素抗癌药理作用机制的研究进展

双氢青蒿素是青蒿素的一种重要衍生物,是我国自行研发的抗疟新药。近年来,人们发现双氢青蒿素不但具有抗疟活性,而且具有良好的抗肿瘤效果,被认为是前景良好的抗肿瘤药。因此,综述目前双氢青蒿素抗肿瘤作用发生机制、靶点和通路的研究进展,主要包括癌细胞凋亡、内质网应激、癌细胞生长增殖、侵袭转移、肿瘤多药耐药以及细胞氧化损伤等方面。为抗肿瘤的基础研究、新药物研发以及药物设计提供参考和依据。     

抗肿瘤药物Vadimezan的合成及其临床研究近况

Vadimezan是一种小分子肿瘤血管生长抑制剂,它具有抑制多种实体瘤的生物活性。本文综述了Vadimezan的最新合成研究进展,并简要介绍了其临床研究近况。     

P53-mediated cell cycle arrest and apoptosis through a caspase-3- independent, but caspase-9-dependent pathway in oridonin-treated MCF-7 human breast cancer cells

Aim： To study the caspase-3-independent mechanisms in oridonin-induced MCF-7 human breast cancer cell apoptosis in vitro. Methods： The viability of oridonin- treated MCF-7 cells was measured by MTT （thiazole blue） assay. Apoptotic cells with condensed nuclei were visualized by phase contrast microscopy. Nucleosomal DNA fragmentation was assayed by agarose gel electrophoresis. The apoptotic ratio was determined by lactate dehydrogenase assay. Cell cycle alternation and mitochondrial membrane potential were measured by flow cytometric analysis. Bax, Bcl-2, caspase-3, caspase-9, heat shock protein （Hsp）90, p53, p-p53, p21, Poly （ADP-ribose） polymerase （PARP）, and the inhibitor of caspase-activated DNase （ICAD） protein expressions were detected by Western blot analysis. Results： Oridonin inhibited cell growth in a time- and dose-dependent manner. Cell cycle was altered through the upregulation of p53 and p21 protein expressions. Pancaspase inhibitor Z-VAD-fmk and calpain inhibitor II both decreased cell death ratio. Nucleosomal DNA fragmentation and the downregulation of △ψmit were detected in oridonin-induced MCF-7 cell apoptosis, which was involved in a postmitochondrial caspase-9-dependent pathway. Decreased Bcl-2 and Hsp90 expression levels and increased Bax and p21 expression levels were positively correlated with elevated levels of phosphorylated p53 phosphorylation. Moreover, PARP was partially cleaved by calpain rather than by capase-3. Condusion： DNA damage provoked alternations in the mitochondrial and caspase-9 pathways as well as p53-mediated cell cycle arrest, but was not related to caspase-3 activity in oridonin-induced MCF-7 cells.     

川芎嗪联合mTOR抑制剂调控卵巢癌SKOV-3细胞增殖、侵袭迁移的实验研究

目的 研究川芎嗪联合mTOR抑制剂对卵巢癌SKOV-3细胞增殖、侵袭迁移的作用.方法 分别设置对照组、40μmol/L川芎嗪组、5μmol/L雷帕霉素组、40μmol/L川芎嗪联合5μmol/L雷帕霉素组,各组SKOV-3细胞给药后继续培养48 h后,MTT法考察各组SKOV-3细胞的增殖抑制率,Transwell实验...     

双氢青蒿素对非小细胞肺癌A549细胞增殖及放疗增敏的影响

目的观察双氢青蒿素(DHA)对非小细胞肺癌A549细胞的影响。方法通过CCK-8法测定双氢青蒿素的IC10,选择低毒剂量IC10作实验浓度,CCK-8法测定DHA对A549细胞增殖的影响,流式细胞术检测DHA对细胞周期及凋亡的影响,平板克隆形成实验检测DHA对放疗敏感性的影响。结果双氢青蒿素的IC10为23.47μmol·L-1,双氢青蒿素能抑制A549细胞增殖,阻滞细胞周期,将细胞周期控制在S期,增加放疗敏感性。结论青蒿素能明显抑制细胞增殖,增加放疗敏感性。     

双氢青蒿素诱导肺癌细胞凋亡的实验研究

双氢青蒿素是半合成的青蒿素衍生物,近年来研究表明青蒿素类药物具有明显抑制肿瘤生长的作用。目的:探讨双氢青蒿素对肺癌细胞生长抑制作用及其机制。方法:以体外培养的SPC-A-1细胞株为研究对象,采用MTT法测定二氢青蒿素对SPC-A-1细胞的增殖影响,采用TUNNEL染色、DNAladder及流式细胞术检测双氢青蒿素诱导SPC-A-1细胞凋亡。结果:DHA对SPC-A-1细胞的抑制增值作用呈浓度依赖性和时间依赖性特点,双氢青蒿素抑制SPC-A-1细胞增殖作用主要由于其诱导肺癌细胞凋亡所致。     

钾通道开放剂比那地尔对卵巢癌细胞增殖及凋亡的影响

目的 研究钾通道开放剂比那地尔对卵巢癌细胞(SKOV3)增殖和凋亡的作用.方法 将比那地尔(浓度分别为10、50、200、500 mmol·L-1)作用于卵巢癌细胞,用MTT法检测细胞活性,采用Hoechest33258荧光染色检测细胞凋亡,同时通过碘化丙啶(PI)染色,采用流式细胞仪检测细胞凋亡比率.结果 比那地尔对SKOV3细胞的增殖抑制效应具有剂量依赖性特点,并能诱导SKOV3细胞凋亡.结论 钾通道对SKOV3细胞增殖具有重要调控作用,钾通道开放剂可促进细胞凋亡.     

奥曲肽抑制人卵巢癌细胞增殖

目的 探讨生长抑素类似物奥曲肽在体内外对人卵巢癌细胞株SKOV3生长的影响.方法 Mtt比色法观察体外奥曲肽对人卵巢癌细胞株SKOV3的生长抑制作用.建立人卵巢癌细胞株SKOV3裸鼠移植瘤模型,随机分成四组,分别给予生理盐水(A组)、奥曲肽(B组)、顺铂(C组)及两药联用(D组)处理,处死裸鼠后采用免疫组织化学法检测肿瘤标本血管内皮生长因子(VEGF)的表达.结果 奥曲肽可抑制体外SKOV3细胞生长,且其作用呈时间、浓度依赖性.各用药组瘤重、瘤体积、VEGF的表达均低于A组(P<0.05).结论 奥曲肽能抑制体内外人卵巢癌细胞株SKOV3生长,对肿瘤VEGF表达的抑制可能为其抑瘤机制之一.     

Emerging growth factor receptor antagonists for ovarian cancer treatment

Introduction: Epithelial Ovarian Cancer (EOC) is the most lethal gynecological malignancy. EOC outcomes remain unsatisfactory despite aggressive surgical approach, disease chemo-sensitivity and recent introduction of agents targeting angiogenesis and tumour genome instability. Advances in EOC research have allowed for a tailored treatment approach and accelerated development of novel treatments strategies from bench to bed side, anticipated to improve patient outcomes.

Areas covered: Comprehensive review of growth factor receptor antagonists for EOC treatment currently in different stages of development was performed. English peer-reviewed articles and abstracts were searched in MEDLINE, PubMed, Embase and major conferences. We focused on agents that antagonize growth factors promoting sustained proliferative signaling, angiogenesis and evasion of immune destruction blocking the receptor or its stimulating factors.

Expert opinion: Receptor signaling has been well characterized for most cancer generating pathways. Growth receptor antagonists are represented by both high receptor affinity monoclonal antibodies as well as tyrosine kinase inhibitors; both are especially effective when a related predictive biomarker of response is identified. Therefore, along with the promising development of novel receptor antagonists or modulators in EOC treatment, targeting essential growth pathways in the tumour and associated microenvironment, is fundamental for biomarker discovery and towards achieving significant improvements in response.     

二氢青蒿素抑制K562细胞血管内皮生长因子的表达

目的通过观察二氢青蒿素抑制K562细胞血管内皮生长因子(VEGF)的表达，探讨青蒿素类药物在抑制血液肿瘤血管新生方面的作用。方法运用MTT法、免疫组化分析和Western blotting分析等探讨了二氢青蒿素对K562细胞增殖以及VEGF表达方面的影响，并进一步对药物预处理后肿瘤细胞的条件培养基在促内皮细胞增殖以及促鸡胚绒毛尿囊膜(CAM)血管新生的作用进行评定。结果二氢青蒿素能有效抑制K562细胞的增殖，并显著下调K562细胞VEGF蛋白和mRNA的表达。同时,药物预处理细胞的条件培养基，其促内皮细胞增殖和促CAM血管新生的能力都有所下降，并呈药物浓度依赖性。结论二氢青蒿素能显著下调K562细胞VEGF的表达，并能抑制由其诱导的血管新生作用。     

卵巢上皮性癌患者血清和腹水中血管上皮因子测定的临床价值

目的 测定卵巢上皮性癌患者血清和腹水中血管上皮生长因子(VEGF)的含量,探讨VEGF在卵巢上皮性癌的诊断、病情监测、预测复发中的价值.方法 采用酶联免疫吸附试验测定卵巢上皮性良性肿瘤(良性组)30例、交界性肿瘤(交界性组)7例、恶性肿瘤(恶性组)33例患者血清和腹水(或腹腔冲洗液)中VEGF的含量.结果 恶性组术前血清和腹水中VEGF的量明显高于交界性组和良性组(P＜0.05);交界性组、恶性组术后血清VEGF的量较术前明显下降(P＜0.05);恶性组Ⅲ～Ⅳ期术前血清VEGF的含量明显高于Ⅰ～Ⅱ期(P＜0.05),病理分级G2-G3的明显高于G1(P＜0.01);10例复发患者血清VEGF的含量明显高于23例未复发者(P＜0.05).结论 血清VEGF水平与卵巢上皮性癌的生长、预后有关,具有肿瘤标记物特性,可作为卵巢上皮性癌的诊断和病情监测指标.     

硼替佐米对卵巢癌SKOV-3/DDP细胞增殖和耐药逆转的影响

目的:探讨硼替佐米对卵巢癌SKOV-3/DDP细胞增殖和耐药逆转的影响和作用机制。方法:采用MTT法检测不同浓度硼替佐米和顺铂(DDP,cisplatin)对SKOV-3/DDP不同作用时间的细胞生长抑制率,以及硼替佐米和DDP合用和单独应用时的细胞生长抑制率;流式细胞术检测细胞凋亡和细胞周期的变化。结果:硼替佐米能够有效抑制SKOV-3/DDP细胞增殖,硼替佐米与DDP合用组的SKOV-3/DDP细胞抑制率较硼替佐米和DDP单用组均明显增强。单独应用硼替佐米细胞周期阻滞于G2/M期,单独应用DDP细胞周期阻滞于S期,两药联合出现更明显的S期阻滞。结论:硼替佐米与DDP具有协同作用,能够逆转SKOV-3/DDP细胞对DDP的耐药性。     

高效液相色谱法测定双氢青蒿素含量

本文研究了双氢青蒿素的β异构体与α异构体转化平衡条件；并采用反相高效液相色谱法对其进行定量测定。色谱条件为：ＹＷＧ－Ｃ１８色谱柱（２００ｍｍ×５ｍｍ，１０μｍ），乙腈－０．０２ｍｏ１／Ｌ硫酸铵溶液－１２％三乙胺溶液（６０：４０：０．２，ｐＨ５．０）为流动相，以萘作内标，检测波长为２１０ｎｍ，本法准确、简便、快速。     

Olaparib,PARP1 inhibitor in ovarian cancer

Introduction: Ovarian cancer is the most important cause of gynecological cancer-related mortality. Conventional treatments for advanced or recurrent disease offer limited results in terms of long-term responses and survival. Researches have recently focused on target therapies, which represent a new, promising, therapeutic approach, able to maximizing tumor kill and minimizing toxicity. The family of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors is currently one of the most hopeful and investigated alternatives.

Areas covered: Preclinical and clinical studies of Olaparib, the most investigated PARP inhibitor in ovarian cancer, are analyzed and discussed. Data were obtained by searching for all English peer-reviewed articles on Medline, on Cochrane Database and all on-going Phase I and II studies registered on National Cancer Institute Clinical Trials; also any related abstracts recently presented on Olaparib at major international congresses will be included.

Expert opinion: Bad prognosis and drug resistance usually affect ovarian cancer. Recent trends toward the knowledge of molecular-specific pathways have produced new target drugs. PARP inhibition mediated by Olaparib in BRCA1 (breast cancer 1) and BRCA2 (breast cancer 2)-mutated and in sporadic ovarian cancer represents a promising field of investigation. Further studies are needed to confirm initial exciting results.