Suppressive effect of RAS inhibitor manumycin A on aberrant crypt foci formation in the azoxymethane-induced rat colorectal carcinogenesis model.

Abstract

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.

METHODS:

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.

RESULTS:

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).

CONCLUSION:

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.

• Authors: Miho Tsuda, Koichi Okamoto, Naoki Muguruma, Katsutaka Sannomiya, Tadahiko Nakagawa, Hiroshi Miyamoto, Shinji Kitamura, Takahiro Goji, Tetsuo Kimura, Toshiya Okahisa, Keisuke Izumi, Tetsuji Takayama
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 28 Issue 10 Pg. 1616-23 (Oct 2013) ISSN: 1440-1746 [Electronic] Australia
• PMID: 23730936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Chemical References

• Enzyme Inhibitors
• Ki-67 Antigen
• Polyenes
• Polyunsaturated Alkamides
• Farnesyltranstransferase
• Extracellular Signal-Regulated MAP Kinases
• ras Proteins
• Azoxymethane
• manumycin

Topics

• Aberrant Crypt Foci (chemically induced, genetics, pathology, prevention & control)
• Animals
• Apoptosis (drug effects)
• Azoxymethane (pharmacology)
• Colorectal Neoplasms (chemically induced, genetics, pathology, prevention & control)
• Disease Models, Animal
• Enzyme Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Farnesyltranstransferase (antagonists & inhibitors)
• Genes, ras (genetics)
• Injections, Subcutaneous
• Ki-67 Antigen (metabolism)
• Mutation
• Phosphorylation (drug effects)
• Polyenes (administration & dosage, pharmacology, therapeutic use)
• Polyunsaturated Alkamides (administration & dosage, pharmacology, therapeutic use)
• Rats
• Rats, Inbred F344
• ras Proteins (antagonists & inhibitors)