共查询到18条相似文献,搜索用时 109 毫秒
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整合素αvβ3拮抗剂的研究进展 总被引:1,自引:0,他引:1
肿瘤生长初期没有新血管生成(无血管期),其生长到一定程度时依赖新生血管的维持.肿瘤血管生成是肿瘤生长和转移的形态学基础,它不仅向肿瘤提供营养,也向宿主输出大量的肿瘤细胞导致肿瘤的生长和转移.因此对以抑制肿瘤血管生成为目的的抗肿瘤药物的研究方兴未艾,有很多具有抑制肿瘤血管生成作用的化合物如大黄素与青蒿琥酯等被发现.整合素αvβ3介导血管内皮细胞和肿瘤细胞的黏附,参与血管生成和肿瘤转移,在肿瘤生长中起重要作用.当其功能受到抑制时,血管内皮细胞出现凋亡,肿瘤生长受到抑制,甚至肿瘤消退.整合素αvβ3受体拮抗剂作为抗新生血管肿瘤药物的同时,对骨质流失、血栓、风湿性关节炎的治疗也起了重要作用. 相似文献
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《中国药理学通报》2017,(8)
转移是恶性肿瘤的重要生物学特征之一,与肿瘤患者的预后紧密相关。近年来研究表明,去整合素-金属蛋白酶8(a disintegrin and metalloprotease 8,ADAM8)在多种恶性肿瘤中呈现高表达状态,且在恶性肿瘤的转移中发挥着重要的作用。研究显示,ADAM8过表达可减弱肿瘤细胞间的黏附作用,并促进细胞外基质(extracellular matrix,ECM)降解和细胞膜上细胞因子释放,同时有助于肿瘤部位新生血管生成,从而促进了肿瘤细胞转移。因此,抑制ADAM8有可能对肿瘤转移产生抑制作用,这使得ADAM8成为恶性肿瘤的预后指标和潜在治疗靶点,备受关注。该文对ADAM8与肿瘤转移的研究进展进行综述,探讨ADAM8介导的肿瘤转移的机制和靶向ADAM8进行肿瘤转移治疗的策略,为后续研究和临床治疗提供重要的参考。 相似文献
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整合素连接激酶(ILK)在肾脏疾病中的研究进展 总被引:1,自引:1,他引:0
整合素连接激酶(integrin-linked kinase,ILK)是一种丝氨酸/苏氨酸蛋白激酶,可与整合素β1、β3亚基胞浆域结合,参与整合素、生长因子、Wnt及TGF-β/Smad等多种信号转导,在调节细胞黏附、凋亡、转移、生长、细胞周期、肿瘤形成等过程中起重要作用。细胞中ILK表达异常,将引发病理变化。本文综述了ILK的生物学活性及其与肾脏疾病的关系,提示ILK的表达调控可能成为治疗肾脏疾病的新途径。 相似文献
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骨桥蛋白是一种分泌的磷酸化蛋白,在调控肿瘤转移发面发挥重要作用,并已作为一种重要的肿瘤标志物用于临床和作为一个潜在的调控肿瘤转移的治疗手段。OPN DNA序列高度保守,其中包含几个重要的功能域包括αvβ整合素和CD44结合位点。高OPN的表达水平与肿瘤的浸润、恶化或转移有关。研究表明,骨桥蛋白介导的分子机制在细胞凋亡,细胞外基质蛋白水解和重塑,细胞迁移,对免疫主细胞的逃逸,新生血管的生成等方面与肿瘤的转移有关。OPN的转录调控是复杂的,涉及到多种途径。现阶段对OPN的生物学知识的了解表明,其在分子水平上治疗肿瘤转移方面很有研究价值。 相似文献
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整合素与肿瘤侵袭和转移的研究进展 总被引:2,自引:0,他引:2
整合素(integrin)分布广泛[1],属于细胞黏附分子家族。研究发现整合素可以调节细胞-细胞、细胞-细胞外基质(extracellu-larmatrix,ECM〕间的黏附。整合素所介导的肿瘤细胞与ECM间的相互作用影响肿瘤的发生、增殖、侵袭和转移到其他组织的能力。现就整合素的结构、功能及其对肿瘤侵袭和转移的影响予以综述。 相似文献
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Li C Lu N Qi Q Li F Ling Y Chen Y Qin Y Li Z Zhang H You Q Guo Q 《Biochemical pharmacology》2011,(12):1873-1883
Cell adhesion plays an important role in the steps of cancer metastasis. Regulation of cell–cell (intercellular) and cell–matrix adhesion is a promising strategy for cancer progression. Gambogic acid is a xanthone derived from the resin of the Chinese plant Garciania hanburyi, with potent anti-metastasis activity on highly metastatic cells. The aim of this study was to investigate the function and mechanism of gambogic acid on tumor adhesion. We found that gambogic acid strongly inhibited the adhesion of human cancer cells to fibronectin. This inhibition was associated with the deformation of focal adhesion complex, which was mediated by suppressing the expression of integrin β1 and integrin signaling pathway. In vitro, cell lipid rafts clustering was inhibited following treatment of gambogic acid, which induced the suppression of integrin β1 and focal adhesion complex proteins colocalization within rafts. Moreover, gambogic acid significantly decreased cellular cholesterol content, whereas cholesterol replenishment lessened the inhibitory effect of gambogic acid on cell adhesion. Real-time PCR analysis showed that gambogic acid reduced mRNA levels of hydroxymethylglutaryl-CoA reductase and sterol regulatory element binding protein-2, while increased acetyl-CoA acetyltransferase-1/2. Taken together, these results demonstrate that gambogic acid inhibits cell adhesion via suppressing integrin β1 abundance and cholesterol content as well as the membrane lipid raft-associated integrin function, which provide new evidence for the anti-cancer activity of gambogic acid. 相似文献
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INTRODUCTION: Integrin receptors for cell adhesion to the extracellular matrix have important roles in all stages of cancer progression and metastasis. Since the integrin family was discovered in the early 1980's, many studies have identified critical adhesion and signaling functions for integrins expressed on tumor cells, endothelial cells and other cell types of the tumor microenvironment, in controlling proliferation, survival, migration and angiogenesis. In recent years, the laminin-binding integrin α3β1 has emerged as a potentially promising anti-cancer target on breast cancer cells. AREAS COVERED: Studies from the past decade that implicate integrins as promising anti-cancer targets and the development of integrin antagonists as anti-cancer therapeutics. Recent preclinical studies that have identified the laminin-binding integrin α3β1 as an appealing anti-cancer target and the knowledge gaps that must be closed to fully exploit this integrin as a therapeutic target for breast cancer. EXPERT OPINION: Although the tumor-promoting functions of α3β1 implicate this integrin as a promising therapeutic target on breast cancer cells, successful exploitation of this integrin as an anti-cancer target will require a better understanding of the molecular mechanisms whereby it regulates specific tumor cell behaviors and the identification of the most appropriate α3β1 functions to antagonize on breast cancer cells. 相似文献
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《Expert opinion on therapeutic targets》2013,17(10):1197-1210
Introduction: Integrin receptors for cell adhesion to the extracellular matrix have important roles in all stages of cancer progression and metastasis. Since the integrin family was discovered in the early 1980's, many studies have identified critical adhesion and signaling functions for integrins expressed on tumor cells, endothelial cells and other cell types of the tumor microenvironment, in controlling proliferation, survival, migration and angiogenesis. In recent years, the laminin-binding integrin α3β1 has emerged as a potentially promising anti-cancer target on breast cancer cells. Areas covered: Studies from the past decade that implicate integrins as promising anti-cancer targets and the development of integrin antagonists as anti-cancer therapeutics. Recent preclinical studies that have identified the laminin-binding integrin α3β1 as an appealing anti-cancer target and the knowledge gaps that must be closed to fully exploit this integrin as a therapeutic target for breast cancer. Expert opinion: Although the tumor-promoting functions of α3β1 implicate this integrin as a promising therapeutic target on breast cancer cells, successful exploitation of this integrin as an anti-cancer target will require a better understanding of the molecular mechanisms whereby it regulates specific tumor cell behaviors and the identification of the most appropriate α3β1 functions to antagonize on breast cancer cells. 相似文献
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Integrins constitute an important class of cell adhesion receptors responsible not only for cell-matrix adhesion but also for signaling bidirectionally across the membrane. Integrins are involved in many biological processes such as angiogenesis, thrombosis, inflammation, osteoporosis and cancer. Integrins thus play a key role in many severe human diseases. In this review we will describe recent research and development of RGD-containing integrin ligands for medical applications including drug design, radiolabeling, drug targeting, as well as biomaterial research. Many ligands have been developed for targeting the avb3 integrin in order to block angiogenesis or osteoporosis, but there are also other integrins like avb5 and a5b1 which become more and more interesting for similar purposes. aIIbb3 constitutes a potent target in thrombosis therapy; but the search for suitable ligands is still ongoing. We will reconstruct the drug development process for these integrin subtypes considering selected examples with focus on structure based design. Different structural requirements are pointed out concerning integrin activity and particularly the selectivity towards the distinct integrin types. Furthermore, we will show recent progress in tumor and thrombosis imaging based on radiolabeled RGD-containing ligands binding avb3 or aIIbb3, respectively. Additionally further advances in biomaterial research are presented. We describe the coating of different implant materials with various avb3 recognizing ligands for the purpose of increasing cell attachment and biocompatibility. 相似文献
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Inhibition of tumor formation by snake venom disintegrin. 总被引:6,自引:0,他引:6
Rong-Sen Yang Chih-Hsin Tang Woei-Jer Chuang Tsang-Hai Huang Hui-Chin Peng Tur-Fu Huang Wen-Mei Fu 《Toxicon》2005,45(5):661-669
The metastasis of tumor cells to bone involves migration, invasion and adhesion to bone. Breast and prostate cancer cells have predilection for spreading to bone. Snake venom-derived arginine-glycine-aspartic acid (RGD)-containing disintegrins (e.g. rhodostomin) have been demonstrated to inhibit cell adhesion. Here, we found that rhodostomin inhibited the adhesion of breast and prostate carcinoma cells to both unmineralized and mineralized bone extracellular matrices in a dose-dependent manner, without affecting the viability of tumor cells. In addition, rhodostomin also inhibited the migration and invasion of breast and prostate carcinoma cells. It specifically inhibited the binding of monoclonal antibody (MoAb) 7E3, which recognizes integrin alphavbeta3, to tumor cells, but not those of other MoAbs against other integrin subunits such as alpha2, alpha3, alpha5 and beta1. As breast cancer cells MDA-MB-231 were locally injected into tibia in nude mice, histological examination of the tibia of control group revealed that most of the cancellous bone had been replaced by the breast cancer cells after 28 days' inoculation. In contrast, co-administration of trigramin with cancer cells markedly inhibited tumor growth and bone destruction. Taken together, disintegrins strongly inhibit the adhesion, migration, invasion of tumor cells and also tumor growth of human breast cancer cells in bone as well. Therefore, disintegrins may be developed as alternate therapy for bone metastasis of cancer cells. 相似文献
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Bhaskar V Fox M Breinberg D Wong MH Wales PE Rhodes S DuBridge RB Ramakrishnan V 《Investigational new drugs》2008,26(1):7-12
Summary Angiogenesis, the process by which new blood vessels form from existing vasculature, is critical for tumor growth and invasion.
Growth factors, such as VEGF, initiate signaling cascades resulting in the proliferation of resting endothelial cells. Blockade
of growth factor pathways has proven effective in inhibiting angiogenesis and tumor growth in vivo. Integrins, including the integrin α5β1, are also important mediators of angiogenesis and these adhesion molecules also regulate
cancer cell growth and migration in vitro. Volociximab is a high affinity, function-blocking antibody against integrin α5β1 that is currently in multiple Phase II
oncology clinical trials. Volociximab displays potent anti-angiogenic activity in a monkey model of choroidal neovascularization.
In this study, we explored the consequences of integrin α5β1 blockade on tumorigenesis. Because volociximab does not cross-react
with rodent α5β1, the syngeneic rabbit VX2 carcinoma model was utilized as an alternative to standard mouse xenograft models
for the assessment of anti-tumor activity of volociximab. Volociximab administered intravenously to rabbits bearing VX2 tumors
is detectable on tumor cells and vasculature 45 min post-administration. Volociximab was found to significantly inhibit the
growth of tumors growing subcutaneously or intramuscularly, despite a 20-fold lower affinity for rabbit integrin, relative
to human. This effect was found to correlate with decreased blood vessel density within these tumors. These results support
the use of volociximab in the intervention of malignant disease. 相似文献
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Integrins are a family of heterodimeric receptors, which modulate many cellular processes including: growth, death (apoptosis), adhesion, migration, and invasion by activating several signaling pathways. Integrin-binding RGD (arginine-glycine-aspartic acid) is found in several important extracellular matrix proteins which serve as adhesive integrin ligands. The RGD motif has also been found in many toxins from snake venom and other sources that specifically inhibit integrin binding function and serve as potent integrin antagonists, particularly of platelet aggregation and integrin-mediated cell adhesion. Many of these proteins have potential as therapeutic agents which can target integrins directly. Structural and functional studies of several RGD-containing toxins suggest that the inhibitory potency of these proteins lies in subtle positional requirements of the tripeptide RGD at the tip of a flexible loop, a structural feature for binding to integrins. In addition, amino acid residues in this loop in close vicinity to the RGD-motif determine the integrin-binding specificity and selectivity. This review will present a review of integrin structure and function, and of disintegrin structural features responsible for their activity as antagonists of integrin function. The use of integrins in drug targeting and integrins as targets for drug delivery by using the RGD as a template structure will also be discussed. 相似文献
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Tian F Zhu CH Zhang XW Xie X Xin XL Yi YH Lin LP Geng MY Ding J 《Molecular pharmacology》2007,72(3):545-552
Vascular endothelial growth factor (VEGF) signaling pathway is essential for tumor angiogenesis and has long been recognized as a promising target for cancer therapy. Current view holds that physical interaction between alpha(v)beta(3) integrin and kinase insert domain-containing receptor (KDR) is important in regulating angiogenesis and tumor development. We have reported previously that a new marine-derived compound, philinopside E (PE), exhibited the antiangiogenic activity via inhibition on KDR phosphorylation and downstream signaling. Herein, we have further demonstrated that PE specifically interacts with KDR extracellular domain, which is distinct from conventional small-molecule inhibitors targeting cytoplasmic kinase domain, to block its interaction with VEGF and the downstream signaling. We also noted that PE markedly suppresses alpha(v)beta(3) integrin-driven downstream signaling as a result of disturbance of the physical interaction between KDR and alpha(v)beta(3) integrin in HMECs, followed by disruption of the actin cytoskeleton organization and decreased cell adhesion to vitronectin. All of these findings substantiate PE to be an unrecognized therapeutic class in tumor angiogenesis and, more importantly, help appeal the interest of the therapeutic potential in angiogenesis and cancer development via targeting integrin-KDR interaction in the future. 相似文献