组织因子途径抑制物-2在非小细胞肺癌中的表达及其与细胞凋亡的关系

目的:探讨非小细胞肺癌中组织因子途径抑制物-2(TFPI-2)的表达及其与细胞凋亡的关系.评价其与肺癌恶性程度的关系.方法:收集非小细胞肺癌石蜡标本、临床资料和临床分期.采用免疫组化法检测TFPI-2蛋白在60例非小细胞肺癌和15例正常肺组织中的表达水平.并应用末端脱氧核苷酸转移酶介导的标记染色法(TUNEL法)检测细胞凋亡,计算凋亡指数(AI).结果:TFPI-2在非小细胞肺癌中的表达指数为60.0%,低于正常肺组织的89.5%.Ⅰ、Ⅱ期及无转移的非小细胞肺癌组织中TFPI.2表达指数(70.9%)及 AI值[(9.58±4.52)%]均高于Ⅲ、Ⅳ期[48.3%、(6.36±1.98)%]及有转移的非小细胞肺癌组织[57.1%、(6.10±2.68)%],差异有统计学意义(P<0.05).结论:TFPI-2在正常肺组织中的表达水平明显高于非小细胞肺癌组织,TFPI-2可能在诱导非小细胞凋亡中起到重要作用.     

Sonoporation induces apoptosis and cell cycle arrest in human promyelocytic leukemia cells

Despite being a transient biophysical phenomenon, sonoporation is known to disturb the homeostasis of living cells. This work presents new evidence on how sonoporation may lead to antiproliferation effects including cell-cycle arrest and apoptosis through disrupting various cell signaling pathways. Our findings were obtained from sonoporation experiments conducted on HL-60 human promyelocytic leukemia cells (with 1% v/v microbubbles; 1 MHz ultrasound; 0.3 or 0.5MPa peak negative pressure; 10% duty cycle; 1 kHz pulse repetition frequency; 1 min exposure period). Membrane resealing in these sonoporated cells was first verified using scanning electron microscopy. Time-lapse flow cytometry analysis of cellular deoxyribonucleic acid (DNA) contents was then performed at four post-sonoporation time points (4 h, 8 h, 12 h and 24 h). Results indicate that an increasing trend in the apoptotic cell population can be observed for at least 12 h after sonoporation, whilst viable sonoporated cells are found to temporarily accumulate in the G₂/M (gap-2/mitosis) phase of the cell cycle. Further analysis using western blotting reveals that sonoporation-induced apoptosis involves cleavage of poly adenosine diphosphate ribose polymerase (PARP) proteins: a pro-apoptotic hallmark related to loss of DNA repair functionality. Also, mitochondrial signaling seems to have taken part in triggering this cellular event as the expression of two complementary regulators for mitochondrial release of pro-apoptotic molecules, Bcl-2 (B-cell lymphoma 2) and Bax (Bcl-2-associated X), are seen to be imbalanced in sonoporated cells. Furthermore, sonoporation is found to induce cell-cycle arrest through perturbing the expression of various cyclin and Cdk (cyclin-dependent kinase) checkpoint proteins that play an enabling role in cell-cycle progression. These bioeffects should be taken into account when using sonoporation for therapeutic purposes.     

Citral inhibits cell proliferation and induces apoptosis and cell cycle arrest in MCF-7 cells

Many natural components of plants extract are studied for their beneficial effects on health and particularly on carcinogenesis chemoprevention. In this study, we investigated the effect of citral (3,7-dimethyl-2,6-octadienal), a key component of essential oils extracted from several herbal plants, on the proliferation rate, cell cycle distribution, and apoptosis of the human breast cancer cell line MCF-7. The effects of this compound were also tested on cyclo-oxygenase activity. Citral treatment caused inhibition of MCF-7 cell growth (IC₅₀-48 h: 18  ×  10⁻⁵  m ), with a cycle arrest in G₂/M phase and apoptosis induction. Moreover, we observed a decrease in prostaglandin E₂ synthesis 48 h after citral treatment. These findings suggest that citral has a potential chemopreventive effect.     

Nakiterpiosin targets tubulin and triggers mitotic catastrophe in human cancer cells

Agents that interfere with mitotic progression by perturbing microtubule dynamics are commonly used for cancer chemotherapy. Here, we identify nakiterpiosin as a novel antimitotic drug that targets microtubules. Nakiterpiosin induces mitotic arrest and triggers mitotic catastrophe in human cancer cells by impairing bipolar spindle assembly. At higher concentration, it alters the interphase microtubule network and suppresses microtubule dynamics. In the presence of nakiterpiosin, microtubules are no longer arranged in a centrosomal array and centrosome-mediated microtubule regrowth after cold depolymerization is inhibited. However, centrosome organization, the ultrastructure of Golgi stacks, and protein secretion are not affected, suggesting that the drug has minimal toxicity toward other cellular functions. Nakiterpiosin interacts directly with tubulin, inhibits microtubule polymerization in vitro, and decreases polymer mass in cells. Furthermore, it enhances tubulin acetylation and reduces viability of paclitaxel-resistant cancer cells. In conclusion, nakiterpiosin exerts antiproliferative activity by perturbing microtubule dynamics during mitosis that activates the spindle assembly checkpoint and triggers cell death. These findings suggest the potential use of nakiterpiosin as a chemotherapeutic agent.     

TKI药物对非小细胞肺腺癌的临床效果观察

目的：探讨T K I药物对非小细胞肺腺癌的临床治疗效果。方法选取非小细胞肺腺癌患者100例，分为两组，使其有可比性。对其临床资料进行回顾分析。观察组患者采取吉非替尼治疗，对照组除不使用吉非替尼外所有治疗均同观察组。对两组患者治疗前后肿瘤大小进行比较，对观察组患者的临床效果进行统计，并记录不良反应发生情况。结果经过治疗，两组患者肿瘤均缩小，其中观察组缩小更为明显。观察组患者随访40个月，死亡31例，中位生存期16．73个月；生存期超过1年者28例（56．00％），35例（70．00％）患者疾病进展或者出现死亡，中位无疾病进展时间12．63个月；16例（32．00％）患者达到部分缓解，中位缓解期11．37个月；20例（40．00％）患者稳定，10例（20．00％）患者进展，还有4例（8．00％）患者疗效未能作出评价。除4例疗效未能作出评价的患者外其余46例患者在接受吉非替尼治疗过程中，其临床疗效受患者年龄、是否吸烟、有无皮疹以及呼吸困难是否加重等因素影响。皮疹是吉非替尼治疗后最常见的不良反应，其次是腹泻，各种不良反应均以Ⅰ度为主，Ⅱ度和Ⅲ度很少。结论吉非替尼作为TKI的代表性药物，在治疗非小细胞肺腺癌方面有确切效果，可以延长患者的生存期，而且不良反应少，容易在临床进行推广。     

Docetaxel induces cell death through mitotic catastrophe in human breast cancer cells

Apoptosis has long been considered to be the prevailing mechanism of cell death in response to chemotherapy. Currently, a more heterogeneous model of tumor response to therapy is acknowledged wherein multiple modes of death combine to generate the overall tumor response. The resulting mechanisms of cell death are likely determined by the mechanism of action of the drug, the dosing regimen used, and the genetic background of the cells within the tumor. This study describes a nonapoptotic response to docetaxel therapy in human breast cancer cells of increasing cancer progression (MCF-10A, MCF-7, and MDA-mb-231). Docetaxel is a microtubule-stabilizing taxane that is being used in the clinic for the treatment of breast and prostate cancers and small cell carcinoma of the lung. The genetic backgrounds of these cells were characterized for the status of key pathways and gene products involved in drug response and cell death. Cellular responses to docetaxel were assessed by characterizing cell viability, cell cycle checkpoint arrest, and mechanisms of cell death. Mechanisms of cell death were determined by Annexin V binding and scoring of cytology-stained cells by morphology and transmission electron microscopy. The primary mechanism of death was determined to be mitotic catastrophe by scoring of micronucleated cells and cells undergoing aberrant mitosis. Other, nonapoptotic modes of death were also determined. No significant changes in levels of apoptosis were observed in response to docetaxel.     

Bortezomib, but not cisplatin, induces mitochondria-dependent apoptosis accompanied by up-regulation of noxa in the non-small cell lung cancer cell line NCI-H460

Defects in the apoptotic machinery may contribute to chemoresistance of non-small cell lung cancer (NSCLC) cells. We have previously showed a deficiency in mitochondria-dependent caspase-9 activation in NSCLC H460 cells after exposure to cisplatin, a drug widely used to treat NSCLC. Here we show that, unlike cisplatin, the novel anticancer agent bortezomib efficiently induces caspase-9 activation and apoptosis in H460 cells. A comparative analysis of molecular events underlying cell death in bortezomib-treated versus cisplatin-treated H460 cells revealed that bortezomib, but not cisplatin, caused a rapid and abundant release of cytochrome c and Smac/DIABLO from mitochondria. This was associated with a marked increase in levels of the BH3-only proapoptotic protein Noxa and the antiapoptotic protein Mcl-1. Taken together, our data show that bortezomib, by promoting a proapoptotic shift in the levels of proteins involved in mitochondrial outer-membrane permeabilization, is a potent activator of the mitochondrial pathway of apoptosis in NSCLC cells. Our preclinical results support further investigation of bortezomib-based therapies as a possible new treatment modality for NSCLC.     

CC10 在非小细胞肺癌中的表达及其与癌细胞凋亡的关系

目的：研究CC10蛋白在非小细胞肺癌（NSCLC）中的表达，并观察其与癌细胞凋亡的关系。方法：采用免疫组化技术检测CC10蛋白在43例NSCLC及20例癌旁正常肺组织石蜡标本中的表达，并借助HPIAS-1000图像系统对结果进行分析。应用TUNEL技术检测43例NSCLC中癌细胞的凋亡情况。结果：CC10蛋白在NSCLC中的表达率为46．5％（20／43），明显低于癌旁正常肺组织的85．0％（P〈0．01）；CC10蛋白在肺癌中的表达水平与分化程度、TNM分期及淋巴结转移有关，但与性别、年龄、肿瘤大小、肿瘤组织学分型无关（P〉0．05）；CC10蛋白阳性的肺癌组织细胞凋亡指数（AI）为（5．585±1．7822）％，CC10蛋白阴性的肺癌组织为（2．856±1．3990）％，差异有显著性，癌细胞AI与NSCLC中CC10蛋白的表达有显著相关性（rs=-0．0211，P〈0．05）。结论：CC10蛋白的表达下调可能在NSCLC的发生发展中起重要作用，NSCLC细胞的凋亡与CC10蛋白的表达下调密切相关     

Synthetic phosphoethanolamine induces cell cycle arrest and apoptosis in human breast cancer MCF-7 cells through the mitochondrial pathway

Phosphoethanolamine (Pho-s) is a compound involved in phospholipid turnover, acting as a substrate for many phospholipids of the cell membranes. In a recent study, we showed that Pho-s has antitumor effect in the several tumor cells. In this study we evaluated the antitumor activity of synthetic Pho-s on MCF-7 breast cancer cells. Here we demonstrate that Pho-s is cytotoxic to MCF-7 cells in a dose-dependent manner, while it is cytotoxic to MCF10 only at higher concentrations. In addition, Pho-s induces a disruption in mitochondrial membrane potential (Δψm). Furthermore, Pho-s induces mitochondria aggregates in the cytoplasm and DNA fragmentation of MCF-7 cells visualized by confocal microscopy. In agreement with the reduction on Δψm, we showed that Pho-s induces apoptosis followed by an increase in cytochrome c expression and capase-3-like activity in MCF-7 cells. Our results demonstrate that Pho-s induces a cell cycle arrest in the G1 phase through an inhibition of cyclin D1 and stimulates p53. An additional highlight of this study is the finding that Pho-s inhibits Bcl-2, inducing apoptosis through the mitochondrial pathway. Taken together, these results show that Pho-s is a promising compound in the fight against cancer.     

晚期非小细胞肺癌耐药检测的研究进展

个体化治疗是近年来非小细胞肺癌(NSCLC)治疗的新理念。肿瘤药敏试验及耐药基因检测可指导临床用药,进行针对性的个体化治疗。本文将对近年来指导个体化治疗的方法作一简单的综述。     

Cetuximab in non-small cell lung cancer

Advanced non-small cell lung carcinoma (NSCLC) remains a challenge to treat due to its high local and systemic recurrence. The overall survival remains poor despite the approval of several new chemotherapeutic agents in the management of advanced NSCLC. Overexpression or mutations in the EGFR have been shown to be associated with a significant percentage of NSCLC. The development of targeted agents, such as cetuximab, against the EGFR is therefore a rational objective. Several preclinical and clinical studies suggest that cetuximab is active against NSCLC. This paper reviews the application of cetuximab in NSCLC.     

Updates in non-small cell lung cancer

Lung cancer is the leading cause of cancer death in both men and women. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, representing more than 80% of lung cancer diagnoses. Five-year survival remains at 15%, but new strategies for prevention, early detection, and treatment may improve survival rates. This article provides an overview of updates in NSCLC, with an emphasis on advances in treatment strategies. Newer targeted therapies, as well as advances in genetic blueprinting, will be discussed. Nurses play a pivotal role in the assessment and management of patients with NSCLC and, therefore, must remain abreast of the most current prevention, screening, and treatment options.     

Tangeretin induces cell cycle arrest and apoptosis through upregulation of PTEN expression in glioma cells

Tangeretin (TANG), present in peel of citrus fruits, has been shown to various medicinal properties such as chemopreventive and neuroprotective. However, the chemopreventive effect of TANG on glioblastoma cells has not been examined. The present study was designed to explore the anticancer potential of TANG in glioblastoma cells and to investigate the related mechanism. Human glioblastoma U-87MG and LN-18 cells were treated with 45 μM concentration of TANG and cell growth was measured by MTT assay. The cell cycle distribution and cell death were measured by flow cytometry. The expression of cell cycle and apoptosis related genes were analyzed by quantitative RT-PCR and western blot. The cells treated with TANG were significantly increased cell growth suppression and cell death effects than vehicle treated cells. Further, TANG treatment increases G₂/M arrest and apoptosis by modulating PTEN and cell-cycle regulated genes such as cyclin-D and cdc-2 mRNA and protein expressions. Moreover, the ability of TANG to decrease cell growth and to induce cell death was compromised when PTEN was knockdown by siRNA. Taken together, the chemopreventive effect of TANG is associated with regulation of cell-cycle and apoptosis in glioblastoma, thereby attenuating glioblastoma cell growth. Hence, the present findings suggest that TANG may be a therapeutic agent for glioblastoma treatment.     

CC10蛋白在非小细胞肺癌中的表达及其与癌细胞凋亡的关系

目的:研究CC10蛋白在非小细胞肺癌(NSCLC)中的表达,并观察其与癌细胞凋亡的关系.方法:采用免疫组化技术检测CC10蛋白在43例NSCLC及20例癌旁正常肺组织石蜡标本中的表达,并借助HPIAS-1000图像系统对结果进行分析.应用TUNEL技术检测43例NSCLC中癌细胞的凋亡情况.结果:CC10蛋白在NSCLC中的表达率为46.5%(20/43),明显低于癌旁正常肺组织的85.0%(P<0.01);CC10蛋白在肺癌中的表达水平与分化程度、TNM分期及淋巴结转移有关,但与性另别、年龄、肿瘤大小、肿瘤组织学分型无关(P>0.05);CC10蛋白阳性的肺癌组织细胞凋亡指数(AI)为(5.585±1.782 2)%,CC10蛋白阴性的肺癌组织为(2.856±1.3990)%,差异有显著性,癌细胞AI与NSCLC中CC10蛋白的表达有显著相关性(rs=-0.0211,P<0.05).结论:CC10蛋白的表达下调可能在NSCLC的发生发展中起重要作用,NSCLC细胞的凋亡与CC10蛋白的表达下调密切相关.     

RASSF10 is epigenetically inactivated and induces apoptosis in lung cancer cell lines

Ras-association domain family 10 (RASSF10), the latest member of the RASSF family with Ras effector function, has been frequently inactivated by aberrant promoter hypermethylation in several human cancers. However, its role in lung cancer has remained unclear. In this study, we investigated the methylation status of RASSF10 by combined bisulfate restriction analysis (COBRA) and examined its preliminary function in lung cancer cell lines. RASSF10 was methylated in four out of six lung cancer cell lines, including NCI-H157, NCI-460, SPCA-1 and NCI-H446. Treatment with a DNA methylation inhibitor, 5-aza-2′-deoxycytiding (5-aza-DC), restored RASSF10 mRNA expression and the restoration of RASSF10 increased cell apoptosis in a dose dependent manner, whereas knockdown of RASSF10 improved cell proliferation ability and inhibited cell apoptosis rate significantly. Immunofluorescence revealed that RASSF10 protein was located in the cell membrane. Taken together, our data for the first time demonstrates the frequent epigenetic inactivation of RASSF10 in lung cancer cell lines. RASSF10 induces cell apoptosis and might function as a tumor suppressor gene in lung cancer.