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Development of effective combinational chemopreventive therapies modulating IGF-1 receptor as a molecular target

开发以 IGF-1 受体为分子靶标的有效联合化学预防疗法

基本信息

批准号：
15590644
负责人：
TSUJII Masahiko
金额：
$ 1.98万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

An inducible isoform of cyclooxygenase (COX),COX-2, insulin-like growth factor (IGF) II, and IGF-I receptor (IGF-IR) are up-regulated in colon carcinoma and might have crucial roles in tumor growth and invasion. The aim of the present study was to investigate the effects of COX-2 inhibitor and drugs blocking the biological activities of angiotensin II [angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs)] on IGF-IR expression and tumor growth in vivo. In vivo, tumor growth and IGF-IR expression were investigated in Colon 26 cells inoculated into BALB/c mice. Celecoxib at the lowest effective dose for suppression of PG production (3 mg/kg) or an ACE inhibitor/ARB alone did not have a significant effect as compared with controls, although a high dose of celecoxib (>20 mg/kg) suppressed tumor growth. On the other hand, combination therapy with these two categories of drugs significantly reduced tumor growth in vivo. Treatment with both celecoxib and an ACE inhibitor/ARB decreased IGF-IR expression levels in inoculated tumor cells. In vitro, IGF-II-induced cell growth and invasion were analyzed in Colon 26. Celecoxib reduced IGF-IR expression and IGF-II-stimulated growth in a dose-dependent manner. PGE(2) or angiotensin II treatment reversed the celecoxib-induced down-regulation of IGF-IR expression, and growth. PGE(2) and angiotensin II-induced Akt phosphorylation, and LY294002 or wortmannin inhibited PGE(2)- or angiotensin II-induced IGF-IR expression, indicating that PGE(2) and angiotensin II both regulate IGF-IR expression by the same Akt/phosphatidylinositol-3 pathway. Thus, combination therapy with NSAIDs and ACE Inhibitors targeting IGF-IR might be a novel and potentially promising strategy for the chemoprevention of colon cancer.

环氧化酶（考克斯）的一种诱导型异构体考克斯-2、胰岛素样生长因子（IGF）II和IGF-I受体（IGF-IR）在结肠癌中表达上调，可能在肿瘤生长和侵袭中起重要作用。本研究的目的是研究考克斯-2抑制剂和血管紧张素II生物学活性阻断剂[血管紧张素转换酶（ACE）抑制剂或血管紧张素II受体阻断剂（ARB）]对IGF-IR表达和肿瘤生长的影响。在体内，肿瘤生长和IGF-IR的表达进行了研究，在结肠癌26细胞接种到BALB/c小鼠。与对照组相比，抑制PG产生的最低有效剂量（3 mg/kg）的塞来昔布或ACE抑制剂/ARB单独使用没有显著效果，尽管高剂量的塞来昔布（>20 mg/kg）抑制了肿瘤生长。另一方面，这两类药物的联合治疗显著降低了体内肿瘤生长。塞来昔布和ACE抑制剂/ARB联合治疗可降低接种肿瘤细胞的IGF-IR表达水平。在体外，IGF-II诱导的细胞生长和侵袭进行了分析，在结肠26。塞来昔布以剂量依赖性方式降低IGF-IR表达和IGF-II刺激的生长。PGE（2）或血管紧张素II治疗逆转了塞来昔布诱导的IGF-IR表达和生长的下调。PGE（2）和血管紧张素II诱导的Akt磷酸化，LY 294002或渥曼青霉素抑制PGE（2）或血管紧张素II诱导的IGF-IR表达，表明PGE（2）和血管紧张素II均通过相同的Akt/磷脂酰肌醇-3途径调节IGF-IR表达。因此，NSAID和ACE抑制剂靶向IGF-IR的联合治疗可能是结肠癌化学预防的一种新的和潜在的有前途的策略。