2004 Fiscal Year Final Research Report Summary
Development of effective combinational chemopreventive therapies modulating IGF-1 receptor as a molecular target
| Project/Area Number |
15590644
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Gastroenterology
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
TSUJII Masahiko Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (40303937)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KAWANO Sunao Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (60133138)
TSUJII Shingo Osaka University, Graduate School of Medicine, Lecture, 医学系研究科, 講師 (40301262)
|
|---|
| Project Period (FY) |
2003 – 2004
|
| Keywords | cyclooxygenase-2 / colon cancer / IGF-I receptor / angiotensin / ACE inhibitor / ARB / Akt / PI3K / celecoxib |
|---|
| Research Abstract |
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.
|
