Suppressive effect of the farnesyltransferase inhibitor for aberrant crypt foci as a precursor of colorectal cancer

Background: Since aberrant crypt foci (ACF) are highly positive for K-RAS mutation, RAS inhibitors are likely to be effective for chemoprevention. However, the chemopreventive effect of RAS inhibitors on colorectal cancer is unknown. Farnesyltransferase inhibitors (FTIs) are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras. In this study, the suppressive effect of a FTI, manumycin A, was investigated on ACF formation. Methods: Male F344 rats injected with AOM were administered manumycin A and examined for ACF in the colorectum. Phosphorylated ERK (p-ERK) and Ki-67 expressions were evaluated by immunohistochemistry. Apoptosis was assessed by TUNEL staining. Results: The mean number of ACF in the 8-week manumycin A group was significantly lower than in the vehicle, and it was significantly lower in the 4-week manumycin A group than in the vehicle (p<0.01). The positive rate for p-ERK in the manumycin A group was significantly lower than in the vehicle (p<0.01). The positive rate for Ki-67 in the manumycin A group was significantly lower than in the vehicle (p<0.01). There were significantly more TUNEL-positive cells in manumycin A group than the vehicle (p<0.05). Conclusion: Manumycin A suppressed ACF formation in the AOM-induced colorectal carcinogenesis model, demonstrating RAS inhibitors may be effective for chemoprevention of colorectal cancer.