具新生血管抑制及血管阻断双重作用的肿瘤血管靶向药物研究进展

以血管新生抑制剂和血管阻断剂为代表的肿瘤血管靶向药物作为一种新的抗肿瘤疗法,其研究与开发已取得显著进展,尤其是二者联用已在临床实践中获得更好疗效。因而,近年来具有新生血管抑制和血管阻断双重作用的肿瘤血管靶向药物研究备受关注。这种具双重作用的肿瘤血管靶向药物因同时保持了血管新生抑制剂和血管阻断剂的各自作用特点,在临床肿瘤治疗上更具优势,不仅能一药多靶,增强抗肿瘤疗效,同时还可降低用药剂量,减少毒副作用,提高用药耐受性,故临床应用前景广阔。综述新生血管抑制剂和血管阻断剂的作用机制及特点,介绍具代表性的兼有新生血管抑制和血管阻断双重作用的肿瘤血管靶向药物研究进展。     

酪氨酸激酶类抗肿瘤作用靶点的研究进展

酪氨酸激酶作为抗肿瘤靶点研究广泛,效果良好,在抗肿瘤领域具有广阔的应用前景。目前已发现的蛋白酪氨酸激酶包括20余个受体酪氨酸激酶家族和10余个非受体酪氨酸激酶家族,他们与肿瘤的发生和发展关系密切。本文主要根据近3年的文献,结合酪氨酸激酶与肿瘤的关系,对酪氨酸激酶类靶点及其抑制剂的研究进展作一综述。     

减毒沙门菌作为人内皮抑素基因载体用于肿瘤基因治疗

减毒沙门菌是一种侵袭性胞内菌,能靶向肿瘤并产生局部抗肿瘤的效应。减毒沙门菌可作为口服基因治疗载体,运载编码有外源基因的真核表达质粒在体细胞内进行持续表达,是一种十分有应用前景的肿瘤治疗剂或媒介。内皮抑素(endostatin)是一种内源性新生血管生成抑制因子,被认为是一种具有应用前景的抗肿瘤因子。此文探讨分析表达人内皮抑素的减毒沙门菌用于肿瘤基因治疗的可行性。     

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。     

抗肿瘤新靶点USP7及其抑制剂的研究进展

泛素-蛋白酶体系统（UPS）的失控与肿瘤、神经退行性疾病、病毒感染等疾病密切相关,以该系统为导向的药物研发已逐渐引发关注,其中蛋白酶体抑制剂硼替佐米（万珂）作为抗肿瘤药物已成功上市。泛素特异性蛋白酶7（USP7）是UPS中的一种关键性酶,作为去泛素化酶参与细胞内肿瘤抑制、DNA修复及免疫应答等过程中诸多重要蛋白的活性调控。本文介绍泛素特异性蛋白酶7及其抑制剂,强调泛素特异性蛋白酶7抑制剂在抗肿瘤治疗中的潜在应用价值。     

选择性B—Raf激酶抑制剂的研究进展

随着细胞分子生物学的发展,肿瘤的分子靶向治疗已成为目前抗肿瘤药物研究的重要领域之一。其中Raf激酶,特刊是B-Raf由于在肿瘤中的突变率高,是目前抗肿瘤药物研充的重要靶点之一。一些Raf抑制剂在早期临床研究中有特犀性抑制活性,显现其具有良好的临床应用前景。     

超抗原SE-金葡菌肠毒素的研究进展

金黄色葡萄球菌肠毒素（SE）是一种外源性超级抗原,仅需微量即能能刺激非特性T细胞的大量增殖,促使产生大量和多种细胞因子及细胞毒,提高机体免疫力,使之获得抗肿瘤的能力,故是一种很有前途的新型肿瘤免疫治疗剂,目前已开始已用于肿瘤患者的辅助治疗。本文对葡萄球菌肠毒素的结构、抗肿瘤作用机理及其应用前景作了简要综述。     

苦参碱抗肿瘤作用研究的新进展

苦参碱作为一种传统的中药成分,具有抗炎、抗病毒、抗心律失常等多种药理作用。近年来,国内外大量研究发现苦参碱在抗肿瘤方面也具有明显功效,能有效地抑制肿瘤细胞增殖、诱导肿瘤细胞分化和程序性细胞死亡、抑制肿瘤侵袭转移、逆转肿瘤多药耐药等。本文对苦参碱抗肿瘤作用的最新研究进展进行综述,表明苦参碱是一种理想的抗肿瘤药物,在癌症治疗中具有良好的临床应用前景。     

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。     

半乳糖凝集素-3多糖类抑制剂的研究进展

半乳糖凝集素-3是近年来抗肿瘤药物研发的热门靶蛋白之一.目前,以半乳糖凝集素-3为靶点的多糖类抑制剂作为抗肿瘤药物的相关研究较多.多糖具有来源广且毒副作用小等特点,具有广阔的医药应用前景.本文综述了以半乳糖凝集素-3为靶点的多糖类抑制剂的研究进展.     

Intracellular signal transduction pathways activated by ceramide and its metabolites.

The sphingolipid ceramide has proven to be a powerful second-signal effector molecule that regulates diverse cellular processes including apoptosis, cell senescence, the cell cycle, and cellular differentiation. Ceramide has been shown to activate a number of enzymes involved in stress signaling cascades including both protein kinases and protein phosphatases. Ceramide kinase targets include stress-activated protein kinases (SAPKs) such as the jun kinases (JNKs), kinase suppressor of Ras (KSR), and the atypical protein kinase C (PKC) isoform, PKC zeta. Ceramide also is capable of activating protein phosphatases such as protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). It is through these protein phosphatases that ceramide can indirectly inhibit kinases that are key components of pro-growth signaling processes such as the classical and novel PKC isoforms and protein kinase B (PKB; also known as Akt). However, the mechanisms how ceramide directly activates enzymes such as JNK and PP2A are still not clear. Elucidation of these mechanisms will reveal how ceramide functions in stress signaling cascades and will provide important information on cellular processes such as apoptosis. It is becoming clear that the ceramide generation is a near universal feature of programmed cell death. It is possible that during at least some apoptotic events, ceramide may be required to activate stress-signal cascades that lead to cell death, while concurrently, suppressing growth and survival pathways in the dying cell. Such a versatile role for ceramide is not unreasonable since ceramide has been implicated as having a role in both intrinsic (i.e. mitochondrial) and extrinsic (i.e. death receptor-mediated) apoptotic pathways. The recent data suggesting that aberrant glycosylation of ceramide (i.e. inactivation of the molecule) may be an important cause of drug resistance in certain cancers suggests that ceramide-mediated signaling cascades are critical components of chemotherapy-induced cell killing. Taken together, these properties of ceramide suggest that this important second-signal molecule may be an important target in anti-neoplastic strategies.     

嗜酸乳杆菌抗肿瘤作用的研究进展

嗜酸乳杆菌（Lactobacillus acidophilus）是机体肠道、生殖道内重要的益生菌之一,与人体健康息息相关。近年来研究发现,该菌在免疫调节中发挥重要作用,并显示出抗肿瘤特性。本文综述了嗜酸乳杆菌对多种癌症的抑制作用,如乳腺癌、胃癌、结肠癌、直肠癌、宫颈癌等,以及对其机体免疫系统的调节、促进肿瘤细胞凋亡、抗炎等抗肿瘤作用机制。本综述为嗜酸乳杆菌抗肿瘤研究、新型抗肿瘤药物的开发和生物防治肿瘤技术的发展提供思路。     

Ceramide transfer protein and cancer

Sphingolipids are important structural components of membranes, and play an equally important role in basic cellular processes as second messengers. Recently, sphingolipids are receiving increasing attention in cancer research. Ceramide is the central molecule that regulates sphingolipid metabolism forming the basic structural backbone of sphingolipids and the precursor of all complex sphingolipids. It is been proposed to be an important regulator of tumor cell death following exposure to stress stimuli. The increase or decrease of ceramide levels leading to change in sensitivity of cancer cells to stress stimuli provides support for a central role of ceramide signaling in cell death. In this review, we have focused on ceramide transfer protein (CERT) as a major regulator of ceramide flux in the cell.     

茯苓抗肿瘤成分研究(Ⅰ)

用硅胶柱层析法从茯苓Poria cocos(Schw.)Wolf的干燥菌核中分离出一种三萜类有机酸,根据理化性质及光谱数据确定为茯苓酸(Pachymic acid),抗肿瘤实验表明茯苓酸对小鼠Sarcoma 180抑制率达62.8％,茯苓中的水溶性低分子量化合物无抗肿瘤活性。     

Delivery systems of ceramide in targeted cancer therapy: ceramide alone or in combination with other anti-tumor agents

ABSTRACT

Introduction: Ceramide is a bioactive lipid which functions as a tumor suppressor, regulating processes such as cell proliferation, differentiation, senescence and apoptosis. However, several challenges need to be overcome in order to realize the therapeutic potential of such a bioactive lipid combination regimen, including the hydrophobic and hemolytic nature of the lipids.

Areas covered: In this review, we briefly describe the biological function of ceramide, then the delivery systems that have been developed to improve the pharmacology of ceramide have been summarized. In addition, combination therapies based on these delivery systems to reveal the interactions between therapeutic drugs and ceramide were also highlighted. Furthermore, future perspective before the extension of ceramide’s applications in cancer treatment will also be discussed.

Expert opinion: Although ceramide has attracted tremendous attention in targeted cancer treatment, its levels are usually suppressed by over-expression of ceramide-metabolizing enzymes or down-regulation of ceramide-generating enzymes. Thus, finding ways to increase ceramide by exogenous treatment in cancer cells is desired. Therefore, translating these bioactive lipids into clinical usage requires a variety of methods, and appropriately designed delivery systems may play the direct and important role in this process.     

丹皮酚抗肿瘤作用机制的研究进展

丹皮酚是牡丹皮的主要活性成分,其抗肿瘤作用的研究已经受到广泛关注。研究报道了丹皮酚对肝癌、胃癌、乳腺癌、卵巢癌等多种肿瘤均具有抗癌作用。丹皮酚主要通过抑制肿瘤细胞增殖,影响肿瘤细胞周期,调控凋亡相关因子及相关通路,抑制肿瘤细胞转移,逆转化疗药物耐药性及放疗增敏发挥抗肿瘤作用。主要综述了丹皮酚抗肿瘤作用机制的最新研究进展。目前丹皮酚抗肿瘤的研究仍处在初步阶段,还需进一步加强对信号转导通路、调控靶点、抑癌基因、联合用药及体内实验等方面的研究。     

Increased effects of MPDAX, a novel xanthine derivative, on antitumor activity of doxorubicin

To clarify the effect of 1-methyl-3-propyl-7-N,N-dimethylpropylamide-xanthine (MPDAX) on doxorubicin (DOX) transport, we examined the efficacy of MPDAX as an amplifier of the antitumor activity of DOX in mice bearing tumors with different properties as to DOX transport across cell membranes. MPDAX significantly enhanced the DOX-induced antitumor activity on DOX-sensitive tumors. It is expected that the increase in antitumor activity caused by MPDAX contributes to the increased DOX concentration in tumors due to the MPDAX-induced change in DOX transport via the transporter expressed in sensitive tumor cells. In contrast, in M5076, a lower sensitive to DOX, MPDAX decreased the tumor weight by half at an otherwise ineffective dose of DOX. Furthermore, in P388/DOX, DOX has no effect, but MPDAX caused an elevation of the DOX-induced antitumor activity with an increase in the DOX concentration in the tumors. The results suggested that MPDAX is a novel amplifier for antitumor agents as it significantly increased the antitumor activity toward tumors with different properties. The DOX concentrations in the MPDAX+DOX group for all tumor lines were about two-fold those in the DOX alone group. Furthermore, MPDAX and DOX exhibited significant inhibitory effects on uridine and thymidine uptake. It is known that nucleoside transporters increase the membrane permeability of DOX. We speculated that MPDAX inhibits the cell membrane transport of uridine and thymidine via nucleoside transporters. MPDAX, acting via nucleoside transporters, increases the DOX-induced antitumor activity toward many tumor types and is an useful biochemical modulator.     

Design, synthesis, and characterization of the antitumor activity of novel ceramide analogues.

A deficiency in apoptosis is one of the key events in the proliferation and resistance of malignant cells to antitumor agents; for these reasons, the search for apoptosis-inducing drugs represents a valuable approach for the development of novel anticancer therapies. In this study we report the first example of conformationally restrained analogues of ceramide (compounds 1-4), where the polar portion of the molecule has been replaced by a thiouracil (1, 3) or uracil (2, 4) ring. The evaluation of their biologic activity on CCRF-CEM human leukemia cells demonstrated that the most active was compound 1 followed by compound 2 (mean 50% inhibition of cell proliferation [IC(50)] 1.7 and 7.9 microM, respectively), while compounds 3 and 4 were inactive, as were uracil, thiouracil, and 5,6-dimethyluracil, the pyrimidine moieties of compounds 1-4. For comparison, the IC(50) of the reference substance, the cell-permeable C2-ceramide, was 31.6 microM. Compounds 1 and 2 and C2-ceramide were able to trigger apoptosis, as shown by the occurrence of DNA and nuclear fragmentation, and to release cytochrome c from treated cells. The treatment of female CD-1 nu/nu athymic mice bearing a WiDr human colon xenograft with the most active compound 1 at 2, 10, 50, and 200 mg/kg ip daily for 10 days resulted in an antitumor effect that was equivalent at 50 mg/kg or superior (200 mg/kg) to that of cyclophosphamide, 20 mg/kg ip daily, delivered on the same schedule, with markedly lower systemic toxicity. In conclusion, the present study demonstrates that the new ceramide analogues 1 and 2 are characterized by in vitro and in vivo antitumor activity and low toxicity.     

Sphingolipid metabolism enzymes as targets for anticancer therapy

Treatment with anti-cancer agents in most cases ultimately results in apoptotic cell death of the target tumor cells. Unfortunately, tumor cells can develop multidrug resistance, e.g., by a reduced propensity to engage in apoptosis by which they become insensitive to multiple chemotherapeutics. Ceramide. the central molecule in cellular sphingolipid metabolism, has been recognized as an important mediator of apoptosis. Moreover, an increased cellular capacity for ceramide glycosylation has been identified as a novel multidrug resistance mechanism. Indeed, virtually all multidrug resistant cell types exhibit a deviating sphingolipid composition, most typically an increased level of glucosylceramide. Thus, the enzyme glucosylceramide synthase, which converts ceramide into glucosylceramide, has emerged as a potential target to increase apoptosis and decrease drug resistance of tumor cells. In addition, several other steps in the pathways of sphingolipid metabolism arc altered in multidrug resistant cells, opening a perspective on additional sphingolipid metabolism enzymes as targets for anti-cancer therapy. In this article, we present an overview of the current understanding concerning drug resistance-related changes in sphingolipid metabolism and how interference with this metabolism can be exploited to over come multidrug resistance.     

Deleted in Colorectal Cancer (DCC) Pathfinding: Axon Guidance Gene Finally Turned Tumor Suppressor

Loss of heterozygosity (LOH) at human chromosome 18q, which includes the gene Deleted in Colorectal Cancer (DCC), has been linked to colorectal and many other human cancers. DCC encodes the receptor for the axon guidance molecule Netrin (Net) and functions during neural development in a variety of organisms. However, since its discovery in the 1990s, the status of DCC as a tumor suppressor has been debated, primarily due to a lack of support for this hypothesis in animal models. A recent study from our laboratory capitalized on the genetic tractability of Drosophila melanogaster to demonstrate that this gene functions as an invasive tumor suppressor, thereby providing the first direct link between DCC loss and metastatic phenotypes in an animal model for cancer. Two subsequent studies from other laboratories have demonstrated that DCC suppresses tumor progression and metastasis in murine colorectal and mammary tumor models. Combined, these findings have prompted the rebirth of DCC as a tumor suppressor and highlighted the need for continued analysis of DCC function in animal models for human cancer.