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Prevention of Induced Colitis in Mice by the Ras Antagonist Farnesylthiosalicylic Acid

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Abstract

Background

Ras proteins are crucial for cell differentiation and proliferation. Targeting Ras with farnesylthiosalicylic acid (FTS), a Ras antagonist, has been suggested as a therapeutic strategy in proliferative and inflammatory diseases.

Aims

To examine the role of Ras and the therapeutic potential of FTS in experimental colitis.

Methods

Colitis was induced in 26 mice by adding 2.5% dextran sodium sulfate to their drinking water for 7 days during which 12 study mice were treated with FTS and 14 control mice were given normal saline. Two additional controls included 10 naïve mice treated with FTS and 7 naïve non-treated mice. The animals were followed clinically and sacrificed after 7 days. Their colons were isolated for histological assessment and for measurement of myeloperoxidase activity (MPO), tumor necrosis factor-α(TNF-α), and interleukin-1β(Il-1β) levels. Ras and activated Ras expression was determined by immunoblotting assays. T cell populations in the colon and spleen were analyzed by flow-cytometry.

Results

FTS induced a 2.1-fold reduction in activated Ras levels (P < 0.004). FTS-treated mice had lower disease activity scores (3.9 ± 1.7 vs. 7.5 ± 2.3, P < 0.001), and lower levels of MPO activity (1.65 ± 0.6 vs. 2.6 ± 0.8 units/g, P < 0.007), Il-1β (2.4 ± 3.6 vs. 24.3 ± 17.5 pg/mg, P < 0.01) and TNF-α (0.63 ± 0.5 vs. 1.9 ± 1 pg/mg, P < 0.04). FTS increased regulatory T cell population in the spleen (1.9 ± 0.4-fold, P < 0.04), and decreased effector T cell populations in the colon and spleen by 24 ± 3% (P < 0.03) and 27 ± 1% (P < 0.02), respectively. FTS had no remarkable side effects.

Conclusions

Ras is involved in the inflammatory processes of induced colitis in mice and its inhibition by FTS ameliorates the severity of the inflammation.

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Authors and Affiliations

  1. Department of Pediatrics, Dana Children’s Hospital, 6 Weizman St., 64239, Tel-Aviv, Israel

    Tal Oron & Shimon Reif

  2. Department of Gastroenerology, Tel Aviv Sourasky Medical Center, 6 Weizman St., 64239, Tel-Aviv, Israel

    Shimon Reif

  3. Department of Pathology, The Sackler School of Medicine, Tel Aviv Sourasky Medical Center, 6 Weizman St., 64239, Tel-Aviv, Israel

    Eli Brazowski

  4. Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978, Tel Aviv, Israel

    Galit Elad-Sfadia, Roni Haklai, Elizabeta Aizman & Yoel Kloog

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  1. Tal Oron
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  2. Galit Elad-Sfadia
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  3. Roni Haklai
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  4. Elizabeta Aizman
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Correspondence to Shimon Reif.

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Oron, T., Elad-Sfadia, G., Haklai, R. et al. Prevention of Induced Colitis in Mice by the Ras Antagonist Farnesylthiosalicylic Acid. Dig Dis Sci 57, 320–326 (2012). https://doi.org/10.1007/s10620-011-1880-y

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  • DOI: https://doi.org/10.1007/s10620-011-1880-y

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