Conflict of interest disclosure: The authors made no disclosures.
Suppressive effect of RAS inhibitor manumycin A on aberrant crypt foci formation in the azoxymethane-induced rat colorectal carcinogenesis model
Article first published online: 23 SEP 2013
© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
Journal of Gastroenterology and Hepatology
Volume 28, Issue 10, pages 1616–1623, October 2013
How to Cite
Tsuda, M., Okamoto, K., Muguruma, N., Sannomiya, K., Nakagawa, T., Miyamoto, H., Kitamura, S., Goji, T., Kimura, T., Okahisa, T., Izumi, K. and Takayama, T. (2013), Suppressive effect of RAS inhibitor manumycin A on aberrant crypt foci formation in the azoxymethane-induced rat colorectal carcinogenesis model. Journal of Gastroenterology and Hepatology, 28: 1616–1623. doi: 10.1111/jgh.12287
Funding sources: This study was partly supported by the Grant of Health, Labour and Welfare Ministry of Japan (No.212-01).
- Issue published online: 23 SEP 2013
- Article first published online: 23 SEP 2013
- Accepted manuscript online: 4 JUN 2013 05:11AM EST
- Manuscript Accepted: 15 MAY 2013
- Health, Labour and Welfare Ministry of Japan. Grant Number: 212-01
- aberrant crypt foci;
- colorectal cancer;
- manumycin A cancer prevention;
- RAS inhibitor
Background and Aim
The chemopreventive effect of RAS inhibitors on colorectal cancer is unknown. Because aberrant crypt foci (ACF), earliest preneoplastic lesions, are highly positive for K-RAS mutation, RAS inhibitors are likely to be effective for chemoprevention. Therefore, in the present study, the suppressive effect of a RAS inhibitor, manumycin A, on ACF formation in an azoxymethane (AOM)-induced rat colorectal carcinogenesis model was investigated.
Rats injected with AOM were administered manumycin A (30 mg/kg) subcutaneously thrice weekly for 8 weeks or for 4 weeks (latter half), sacrificed at 8 weeks, and examined for ACF in the colorectum. Phosphorylated ERK and Ki-67 expression was evaluated by immunohistochemistry. Apoptosis was assessed by TUNEL staining.
The mean number of ACF in the 8-week manumycin A group (72.9 ± 20.1) was significantly lower than in the vehicle group (155.6 ± 56.7, P < 0.01), and it was significantly lower even in the 4-week manumycin A group than in the vehicle group (92.2 ± 13.0 vs 222.3 ± 83.3, P < 0.01). The positive rate for phosphorylated ERK in the manumycin A group (13.5 ± 19.2%) was significantly lower than in the vehicle group (50.2 ± 19.8%, P < 0.01). The positive rate for Ki-67 in the manumycin A group (2.2 ± 3.4%) was significantly lower than in the vehicle group (14.7 ± 8.2%, P < 0.01). There were significantly more terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in tissue samples from the manumycin A group versus the vehicle group (8.6 ± 9.7% vs 2.9 ± 2.0%, P < 0.05).
Manumycin A suppressed ACF formation in the AOM-induced colorectal carcinogenesis model, demonstrating that RAS inhibitors may be very effective for chemoprevention of colorectal cancers.