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

Authors

  • Miho Tsuda,

    1. Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Koichi Okamoto,

    1. Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Naoki Muguruma,

    1. Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Katsutaka Sannomiya,

    1. Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Tadahiko Nakagawa,

    1. Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Hiroshi Miyamoto,

    1. Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Shinji Kitamura,

    1. Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Takahiro Goji,

    1. Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Tetsuo Kimura,

    1. Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Toshiya Okahisa,

    1. Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Keisuke Izumi,

    1. Department of Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Tetsuji Takayama

    Corresponding author
    • Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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  • Conflict of interest disclosure: The authors made no disclosures.
  • Funding sources: This study was partly supported by the Grant of Health, Labour and Welfare Ministry of Japan (No.212-01).

Correspondence

Professor Tetsuji Takayama, Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan. Email: takayama@clin.med.tokushima-u.ac.jp

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.

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