Patients with long-standing
ulcerative colitis (UC) have an increased risk for developing
colorectal cancer (CRC) compared to the general population. For investigation of the mechanisms and prevention of UC and UC-related CRC, establishment of a promising animal model for such disease is important.
1-hydroxyanthraquinone (1-HAQ) present in certain medicinal plants such as Rubia tinctorum L. is a genotoxic and rodent colon
carcinogen. Long-term feeding of
1-HAQ induced hyper-cell proliferation in rat colonic crypts with ulcerative changes, crypt
abscess, severe
inflammation and erosion before the occurrence of
tumors, which are similar to those found in human UC. In addition,
1-HAQ has a synergistic effect with methylazoxymethaol (MAM)
acetate on colon
carcinogenesis. The polymerase chain reaction-single strand conformation polymorphism analysis revealed no mutations in Ki-ras and p53 in
colonic neoplasms induced by MAM
acetate +
1-HAQ, MAM
acetate alone or
1-HAQ alone. Also, no mutations of APC were found in these
tumors. These findings are similar to those found in human
ulcerative colitis-associated
colon cancer in contrast with sporadic
colon cancers. A previous study revealed that induced colonic
tumors had
beta-catenin mutation with high frequency, suggesting
tumor development by activation of the
beta-catenin-Tcf signaling pathway. Increased expression in
TNF-alpha and IL-1alpha was found in these induced
colonic neoplasms, and the expression was more remarkable in colonic mucosa of rats exposed to MAM
acetate +
1-HAQ, MAM
acetate or
1-HAQ when compared with that in untreated rats. Thus, these
cytokines may act as
growth factors in rat colon
carcinogenesis by MAM
acetate and
1-HAQ and the synergistic effect of
1-HAQ with MAM
acetate might be related to the
biological effects of the
cytokines expressed in the inflammatory conditions induced by
1-HAQ.