榄香烯在抑制肿瘤血管生成中的作用

榄香烯是一种广谱的非细胞毒性抗肿瘤药物,能通过下调血管内皮生长因子(VEGF)表达、诱导血管内皮细胞凋亡、抑制肿瘤细胞生长等方面来抑制肿瘤血管生成.有望成为理想的抗肿瘤血管生成药物,但其具体机制尚需深入研究.     

胆管癌中Livin蛋白和血管内皮生长因子的表达及与Caspase-3的相关性研究

目的：探讨凋亡抑制因子Livin蛋白和血管内皮生长因子（vascular endothelial growth factor,VEGF）在胆管癌组织中的表达及与Caspase-3的相关性.方法：采用免疫组化SP法检测80例胆管癌及30例正常胆管组织（取自其他良性疾病行胆管切除者）中Livin蛋白、VEGF及Caspase-3的表达.结果：胆管癌组织中Livin蛋白和VEGF的表达明显高于正常胆管组织（P=0.00）,Caspase-3的表达低于正常胆管组织（P=0.04）;在胆管癌组织中Livin蛋白、VEGF的表达具有正相关性（r=0.532,P=0.00）,Livin蛋白、VEGF的表达均与Caspase-3的表达呈负相关关系（r=-0.668,P=0.00;r=-0.371,P=0.01）.结论：Livin蛋白、VEGF在胆管癌组织中均高表达及两者呈正相关性,表明两者在胆管癌的发生发展中可能起重要作用并且可能发挥协同作用,二者的表达均与Caspase-3的表达呈负相关关系,提示二者均可能是通过抑制凋亡来参与胆管癌的发生发展.     

非小细胞肺癌的分子靶向药物治疗

肺癌是一种高发病率的肿瘤。目前已知表皮生长因子受体（EGFR）、血管内皮生长因子（VEGF）在非小细胞肺癌中有过表达，这种存在于肿瘤组织的过表达通过下游的信号传导能导致肿瘤细胞的增生、血管的生长，凋亡受抑制。表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）通过抑制酪氨酸激酶，抗EGFR单克隆抗体通过和EGFR自身配体竞争受体及抗VEGF单克隆抗体通过和其形成复合物而阻断其信号通路的传导来达到控制肿瘤增生和发展的目的，仅有少许可耐受的不良反应。TKI对东方人NSCLC疗效，腺癌、不吸烟和女性的疗效好可能和其EGFR基因的高突变率相关。但其和化疗合用未显示增加化疗的效果。抗EGFR及VEGF单克隆抗体与化疗合用均显示了一定的效果。就非小细胞肺癌来说，靶向治疗已成为了另一种有效的全身治疗。     

凋亡抑制蛋白Livin在肿瘤治疗中的新进展

Livin是凋亡抑制蛋白的一个新成员,可以编码抑制凋亡的负性调节蛋白。Livin在大多数肿瘤中高表达,体内外研究发现其表达降低可以增加肿瘤细胞凋亡,降低肿瘤细胞的生长潜能,增加肿瘤细胞对化疗的敏感性。因此,Livin可以作为肿瘤治疗的新的靶点。     

CXCR4单克隆抗体抑制乳腺癌MCF-7细胞裸鼠移植瘤的实验研究

目的：研究CXC趋化因子受体4（CXC chemokine receptor 4,CXCR4）单克隆抗体（CXCR4 mAb）对人乳腺癌MCF-7细胞裸鼠皮下移植瘤生长的影响,并初步探讨CXCR4 mAb抗肿瘤的作用机制。方法：采用8周龄Balb/c雌性裸鼠,建立乳腺癌MCF-7细胞裸鼠皮下移植瘤模型。运用CXCR4 mAb进行干预,从整体水平观察CXCR4 mAb对肿瘤生长的影响,采用免疫组织化学法检测肿瘤组织中增殖细胞核抗原（PCNA）、半胱氨酸天冬氨酸酶3（Caspase-3）和血管内皮细胞生长因子（VEGF）的表达情况。结果：CXCR4 mAb可明显抑制移植瘤的生长,瘤体抑制率达到71.4%;CXCR4 mAb治疗后的肿瘤组织中PCNA和VEGF表达明显下降,而Caspase-3表达上升。结论：CXCR4 mAb可能是通过抑制肿瘤细胞增殖、促进肿瘤细胞凋亡及抑制肿瘤血管形成而发挥抗肿瘤生长的作用。     

血管内皮生长因子反义RNA对裸鼠食管癌细胞增殖和凋亡的影响意义

目的：研究血管内皮生长因子（VEGF）反义RNA对裸鼠食管癌移植瘤细胞增殖和凋亡的影响。方法：将转染VEGF反义eDNA和空载体peDNA3．1的食管癌细胞株TE-1分别接种在裸鼠体内；应用免疫组化法、RT-PCR法检测移植瘤组织中VEGF蛋白和mRNA表达情况；流式细胞仪和透射电镜检测肿瘤细胞增殖及凋亡情况。结果：反义组肿瘤组织中VEGF蛋白和mRNA的表达降低，肿瘤细胞的细胞器发生扩张和肿胀、核染色质边集、凝集成块等凋亡形态学改变；Go／G，期细胞明显增多，S期细胞明显减少，细胞增殖指数降低；对照组和空载体组细胞凋亡较少。结论：VEGF反义RNA能抑制裸鼠食管癌细胞的增殖，诱导细胞凋亡，为食管癌基因治疗基础研究提供依据。     

乳腺癌中Livin的表达与癌细胞凋亡相关性的研究

目的：探讨凋亡抑制基因Livin在乳腺癌组织中的表达与细胞凋亡的关系。方法：采用逆转录-聚合酶链反应（RT—PCR）技术检测乳腺癌组织中LivinmRNA的表达,并用westernblot分析Livin蛋白的表达。应用流式细胞术检测乳腺癌细胞的凋亡水平。结果：40例乳腺癌组织中有26例Livin表达,阳性率为65．00％,而13例癌旁正常乳腺组织中Livin低表达,阳性率为15．39％（P〈0．01）。40例乳腺癌组织中,26例乳腺癌组织Livin表达阳性者,肿瘤细胞早期细胞凋亡率为（4．27±0．72）％;14例Livin表达阴性者,肿瘤细胞早期细胞凋亡率为（4．56±0．76）％,两者比较差异有显著性（P〈0．05）。结论：Livin在乳腺癌组织中的异常表达与乳腺癌细胞凋亡有关,有望成为乳腺癌基因治疗的新靶点。     

凋亡抑制蛋白Livin在食管癌中的研究进展

Livin是新近发现的人类IAP家族成员,为类内源性细胞凋亡抑制蛋白,Livin在多种肿瘤细胞中高表达,通过抑制caspase在许多物种中起着抑制细胞凋亡的作用.近年来人们发现Livin特异性表达于食管癌细胞中,通过下调或抑制Livin基因的表达及诱导产生特异性地识别Livin的抗体可抑制、杀死肿瘤细胞,为食管癌的诊断、细胞和基因靶向治疗等提供新的方法.     

凋亡抑制蛋白Livin在肿瘤治疗中的新进展

Livin是凋亡抑制蛋白的一个新成员,可以编码抑制凋亡的负性调节蛋白.Livin在大多数肿瘤中高表达,体内外研究发现其表达降低可以增加肿瘤细胞凋亡,降低肿瘤细胞的生长潜能,增加肿瘤细胞对化疗的敏感性.因此,Livin可以作为肿瘤治疗的新的靶点.     

Livin反义寡核苷酸对人乳腺癌细胞株MCF-7增殖和凋亡影响的研究

目的：探讨Livin mRNA反义寡核苷酸（ASODN）对人乳腺癌MCF-7细胞抑制增殖及诱导凋亡的影响。方法：设计合成特异性的Livin硫代磷酸ASODN及其对照错义寡核苷酸（MSODN），脂质体转染至培养的MCF-7细胞。采用MTT法检测Livin ASODN对MCF-7细胞的增殖抑制作用，RT-PCR检测Livin mRNA的表达水平，电镜、流式细胞仪与吖啶橙／溴化乙锭（AO／EB）细胞染色法检测细胞凋亡水平和形态学改变。结果：Livin ASODN在终浓度为600nmol／L作用MCF-7细胞48h时，能明显地抑制其增殖（IC50=604.4），降低Livin mRNA的表达;电镜、流式细胞仪与A0／EB细胞染色法则表明MCF-7细胞在形态学上出现明显的凋亡改变，细胞凋亡率显著增加，而对照组寡核苷酸未见抑制效应。结论：Livin ASODN能够特异性下调MCF-7细胞中Livin基因表达，在诱导肿瘤细胞凋亡、抑制增殖中发挥重要作用。     

siRNA directed against Livin inhibits tumor growth and induces apoptosis in human glioma cells

Livin, a novel member of the human inhibitors of apoptosis protein family, plays an important role in tumor progression and occurrence by inhibiting cell apoptosis. It is selectively expressed in the most common human neoplasms and appears to be involved in tumor cell resistance to chemotherapeutic agents. The present study was designed to investigate the potential of using RNA interference (RNAi) technique to downregulate Livin expression, and the subsequent effect on human glioma cells. The results showed that knockdown of Livin expression by short interfering RNA (siRNA) significantly inhibited glioma cell proliferation and increased cell apoptosis through cell arrest in the G₁/G₀ phase of cell cycle in vitro. Furthermore, Livin siRNA significantly suppressed tumor growth in nude mice. Together, these findings suggest that RNAi-mediated downregulation of Livin expression could lead to potent antitumor activity in glioma cells and might serve as a novel therapeutic strategy in clinic.     

Antisense oligonucleotide targeting Livin induces apoptosis of human bladder cancer cell via a mechanism involving caspase 3

Background and Aim

in recent years, Livin, a new member of IAPs family, is found to be a key molecule in cancers. Researchers consider Livin may become a new target for tumor therapy; however, the role of it in bladder cancer is still unclear. The purpose of this article is to investigate Antisense Oligonucleotide (ASODN) of Livin on treating bladder cancer cell and underlying mechanisms.

Methods

Phosphorathioate modifying was used to synthesize antisense oligonucleotides targeting Livin, followed by transfection into human bladder cancer cell 5637. After transfection, Livin mRNA and protein level, cell proliferation and apoptosis changes, caspase3 level and its effect on human bladder cancer transplantable tumor in nude mice were measured.

Result

results showed Livin ASODN effectively inhibited Livin expression and tumor cell proliferation, and these effects probably through enhanced caspase3 activity and apoptosis of tumor cells. In nude mice transplantable tumor model, Livin expressions were inhibited meanwhile caspase3 expression was increased. Tumor growth slowed down and apoptosis was enhanced.

Conclusion

Our data suggest that Livin plays an important role in inhibiting apoptosis of bladder cancer cells. Livin ASODN may promote cell apoptosis, inhibit bladder cancer growth, and become one of the methods of gene therapy for bladder cancer.     

Livin/ML-IAP as a new target for cancer treatment

Livin is a member of the inhibitors of apoptosis protein (IAP) gene family, which encodes negative regulatory proteins that prevent cell apoptosis. Livin is selectively expressed in the most common human neoplasms and appears to be involved in tumor cell resistance to chemotherapeutic agents. Several studies in vitro and in vivo have demonstrated that down-regulation of Livin expression increases the apoptotic rate, reduces tumor growth potential and sensitized tumor cells to chemotherapeutic drugs. This review will focus on the role of this protein during cancer development and progression and will demonstrate possible targets for cancer therapy.     

Silencing Livin gene expression to inhibit proliferation and enhance chemosensitivity in tumor cells

Livin, a novel member of the human inhibitors of apoptosis protein (IAP) family, plays an important role in tumor progression and occurrence by inhibiting cell apoptosis. It is selectively expressed in the most common human neoplasms and appears to be involved in tumor cell resistance to chemotherapeutic agents. To investigate its possibility as a therapeutic target for human malignancies, we established two genetically different stable tumor cell lines (LoVo and SPCA-1) and RNA interference (RNAi) technique was employed to downregulate Livin expression in two human tumor cell lines. The specific downregulation of Livin expression in tumor cell lines significantly inhibited in vitro cell proliferation and in vivo tumorigenicity. Furthermore, Livin knockdown led to cell arrest in the G(1)/G(0) phase of cell cycle, eventual apoptosis and chemosensitivity enhancement in tumor cells. All these results indicate that RNAi-mediated downregulation of Livin expression can lead to potent antitumor activity and chemosensitizing effects in human cancers.     

Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function

There is considerable controversy concerning the importance of tumor-derived angiogenic factors to the neovascularization of solid tumors. Tumor, endothelial, and stromal expression of vascular endothelial growth factor (VEGF) have been hypothesized to be critical for tumor angiogenesis. To determine the relative contribution of tumor versus nontransformed tissue expression of VEGF to tumor growth, we used gene targeting and cre-loxP recombination to generate embryonic stem cell lines in which VEGF can be conditionally deleted. These lines were used to derive mouse embryonic fibroblast lines with null mutations in both alleles of VEGF. Upon immortalization and H-ras transformation, we used these VEGF null fibroblasts to make fibrosarcomas in immunocompromised mice. We report that tumorigenic VEGF expression is critical for ras-mediated tumorigenesis, and the loss of tumorigenic expression causes dramatic decreases in vascular density and vascular permeability and increases in tumor cell apoptosis.     

凋亡抑制因子Livin在肺癌组织和血清中的表达

目的：探讨凋亡抑制蛋白Livin在非小细胞肺癌组织和血清中的表达及其与组织类型、临床分期的关系。方法：采用免疫组化法和酶联免疫吸附法（ELISA）分别对40例肺癌组织和血清,20例癌旁组织和良性病变组织,20例健康者血清中Livin的表达水平进行检测。结果：非小细胞肺癌患者组织和血清中Livin水平明显高于对照组（P〈0．05）;组织中Livin蛋白的表达与淋巴结转移有关,但与肺癌临床分期、病理类型、分化程度无关。血清中Livin水平与淋巴结转移、临床分期有关,但与病理类型、分化程度无关;组织和血清间Livin水平无相关性。结论：Livin作为一种新的凋亡抑制蛋白,对非小细胞肺癌诊断、淋巴结转移的判断具有一定的临床价值。     

Inhibition of angiogenesis by blocking activation of the vascular endothelial growth factor receptor 2 leads to decreased growth of neurogenic sarcomas.

Neurogenic sarcomas are incurable, common malignant human peripheral nerve tumors subject to local recurrence and systemic metastasis. In this study, the vascularity, vascular endothelial growth factor (VEGF) expression, and effects of inhibiting VEGF receptor on growth of neurogenic sarcomas were examined. Vascularization and VEGF expression were 6.4- and 15-fold higher in tumors than in normal nerves. The small molecule inhibitor (SU5416) of VEGF receptor 2 had no effect on neurogenic sarcoma cell lines in vitro, but the growth of a human tumor explant xenograft model was reduced by 54.8% compared to vehicle. Reduction in tumor growth was due to decreased tumor angiogenesis, leading to reduction of tumor cell proliferation and increased apoptosis. Inhibiting VEGF function may therefore be a useful adjuvant therapy for neurogenic sarcomas.