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

backgroundRas 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.

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

methodsColitis 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.

resultsFTS 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.

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