Prevention of induced colitis in mice by the ras antagonist farnesylthiosalicylic acid.

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.