Molecular mechanism of tissue factor-induced inhibition of apoptosis in lung cancer cells that are resistant to anti-cancer therapy

组织因子诱导抑制抗癌治疗耐药肺癌细胞凋亡的分子机制

基本信息

批准号：
13670597
负责人：
GABAZZA Esteban
金额：
$ 2.3万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Background : Patients with lung cancer are currently treated with a combination of several anti-cancer drugs. However, the occurrence of resistance to chemotherapy generally limits its efficacy in clinical practice. Thus, the mechanism by which resistance to chemotherapy develops is presently the focus of many investigations. So far,-we have demonstrated that the coagulation system plays important role in the pathogenesis of several lung diseases. For example, we have reported that the circulating level of tissue factor is significantly correlated with survival and clinical stage, of patients with lung cancer, and that it is closely associated with the malignant potential of lung cancerAim : In the present investigation we focused on the intracellular pathway associated with tissue factor expression in lung cancer, and evaluated the relationship between the inhibition of apoptosis and resistance to chemotherapy. In addition, we have also assessed the expression, of the inhibitor of fib … More rinolysis, thrombin-activatable fibrinolysis inhibitorMethod : In the experiments, we used highly sensitive lung cancer cell lines (PC/9. PC7/P, PC14/P, H69/P) and those with high resistance to anticancer drug (PC9/CDDP, PC7/CDDP, PC 14/CDDP, H69/CDDP). The expression of tissue factor and thrombin-activatable fibrinolysis inhibitor was evaluated by enzyme-linked immunoassay and reverse transcriptase polymerase chain reactionResults : Lung cancer cell lines with resistance to anticancer drugs showed increased expression of tissue factor compared to sensitive cell lines. By contrast, cell lines with resistance to chemotherapy showed lower expression of thrombin-activatable fibrinolysis inhibitor than those with high sensitivity to cytotoxic drugs. In addition, the intracellular apoptotic pathway was inhibited in resistant lung cancer cells but not in sensitive cellsConclusion : These results suggest that both tissue factor,and thrombin-activatable fibrinolysis inhibitor are involved in the mechanism of resistance to chemotherapy in lung cancer. Tissue factor and thrombin-activatable fibrinolysis inhibitor may constitute potential indicator of resistance to chemotherapy in patients with lung cancer Less

背景：目前肺癌患者采用多种抗癌药物联合治疗，但化疗耐药的发生通常限制了其在临床实践中的疗效，因此，化疗耐药的产生机制是目前研究的焦点。到目前为止，我们已经证明凝血系统在多种肺部疾病的发病机制中发挥着重要作用，例如，我们报道了组织因子的循环水平与患者的生存和临床分期显着相关。且与肺癌密切相关目的：在本研究中，我们重点关注肺癌组织因子表达的细胞内通路，并评估了细胞凋亡的抑制与化疗耐药之间的关系。此外，我们还评估了肺癌组织因子表达的相关性。纤维蛋白溶解抑制剂，凝血酶激活的纤维蛋白溶解抑制剂方法：在实验中，我们使用高度敏感的肺癌细胞系（PC/9、PC7/P、PC14/P、H69/P）和那些抗癌药物高耐药（PC9/CDDP、PC7/CDDP、PC 14/CDDP、H69/CDDP）。通过酶联免疫分析和逆转录酶聚合酶链反应评估组织因子和凝血酶激活纤溶抑制剂的表达结果：与敏感细胞系相比，对抗癌药物具有抗性的肺癌细胞系表现出组织因子表达增加，相比之下，对化疗具有抗性的细胞系表现出较低的组织因子表达。此外，耐药肺癌细胞的细胞内凋亡途径受到抑制，但敏感细胞则不然。结论：这些结果表明组织因子和凝血酶激活的纤溶抑制剂都参与其中。组织因子和凝血酶激活纤溶抑制剂可能构成肺癌患者化疗耐药的潜在指标。