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:
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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)
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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
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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)
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