Related Experiment Videos
Piroxicam-induced regression of intestinal adenomatous polyps in APC(delta474) mice
Z F Qiu1, K Maruyama, K Sunayama
1Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Abstract:
Mutation of adenomatous polyposis coli (APC) gene results in incidence or development of polyps and colorectal cancer. It has been reported that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cell growth, cause cell cycle arrest, and induce apoptosis. The aims of this study are to investigate chemopreventive effects of piroxicam and elucidate its mechanism. All APC(delta474) mice have intestinal polyps. Thirty-five APC(delta474) mice were divided into three groups: 0.005% solution of piroxicam in tap water was given for P group (n = 15) and 0.001% solution for P' group (n = 5), and water without piroxicam for C group (n = 15) from 4 weeks of age to 12 weeks, respectively. All mice were sacrificed at the 12th week after birth. Hematoxylin-eosin staining for number and size of polyps, immunohistochemical staining for cyclooxygenase (COX)-1 and -2, proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), TUNEL method, and Western blot analysis of COX-2 and VEGF were performed. Polyps were divided into two types of large polyps of >or=300 microm in diameter and small polyps of <300 microm. The number of large polyps in P group decreased significantly compared with C group (p <.0001), but without significant difference in small polyps. There were no significant differences in PCNA index in both of large and small polyps among the three groups. Apoptotic index of polyps in P group increased more than those in C group (p <.05). There was immunohistochemically no significant difference in COX-1 positivity of normal intestinal epithelia and adenomas among three groups. Both numbers of VEGF-positive cells and COX-2 positive cells in the stroma of the small intestine were significantly downregulated in P group (p <.05). COX-2 expression was inhibited in dose-dependent manner without significant difference. There were no significant differences in VEGF expression between P' and C groups. In conclusion, piroxicam suppressed the development of large polyps in APC(delta474) mice by inducing apoptosis and inhibiting VEGF expression in interstitial cells of polyps.
Insights
Piroxicam, a nonsteroidal anti-inflammatory drug (NSAID), significantly reduced large intestinal polyps in APC(delta474) mice. This chemopreventive effect was achieved by increasing apoptosis and decreasing vascular endothelial growth factor (VEGF) expression.
Area of Science:
- Oncology
- Pharmacology
- Gastroenterology
Background:
- Adenomatous polyposis coli (APC) gene mutations are linked to colorectal polyps and cancer.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit anti-proliferative and pro-apoptotic properties.
- Piroxicam is an NSAID with potential chemopreventive applications.
Purpose of the Study:
- To investigate the chemopreventive effects of piroxicam on intestinal polyps in APC(delta474) mice.
- To elucidate the underlying mechanisms of piroxicam's action, including its impact on apoptosis and key molecular markers.
- To assess the dose-dependent effects of piroxicam.
Main Methods:
- APC(delta474) mice were administered varying concentrations of piroxicam or a control solution.
- Histopathological analysis (Hematoxylin-eosin staining) quantified polyp number and size.
- Immunohistochemistry and Western blot analysis assessed cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF), and proliferating cell nuclear antigen (PCNA) expression.
- TUNEL assay determined the apoptotic index of polyps.
Main Results:
- Piroxicam significantly reduced the number of large polyps (>or=300 microm) in a dose-dependent manner.
- An increased apoptotic index was observed in polyps from piroxicam-treated mice.
- Downregulation of cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) expression in polyp stroma was noted.
- No significant changes in PCNA index or COX-1 expression were observed.
Conclusions:
- Piroxicam demonstrates chemopreventive efficacy against large polyp development in a mouse model of intestinal polyposis.
- The mechanism involves the induction of apoptosis and inhibition of VEGF expression.
- These findings suggest piroxicam's potential as a therapeutic agent for APC-related polyp prevention.