Effect of Targeting Janus Kinase 3 on the Development of Intestinal Tumors in the Adenomatous Polyposis Coli^min Mouse Model of Familial Adenomatous Polyposis

Abstract

Familial adenomatous polyposis (FAP) is associated with germ-line mutations in the tumor suppressor gene, adenomatous polyposis coli (APC) located on chromosome 5q21. Multiple intestinal neoplasia (Min) in mice resembles FAP in humans, resulting from a single point mutation in the murine homolog of the APC gene. The effects of the rationally-designed Janus kinase 3 (JAK3) inhibitor JANEX-1 (4(4'-hydroxyphenyl) amino-6,7-dimethoxy-quinazoline, WHI-P131, CAS 202475-60-3) on the development of intestinal tumors in the APC (min/+) mouse model of FAP were examined. The Min mice were fed with rodent chow or chow supplemented with JANEX-1 once a week starting at 1.5 months of age. The cumulative proportions of mice remaining alive at 7 months were 13 ± 6% for control mice versus 72 ± 12% for JANEX-1 treated mice (P<0.0002). In contrast, Compound DDE24, a synthetically activated genistein, an inhibitor of Epidermal Growth Factor receptor (EGF-R), cellular homologue of oncogene product from Raus Avian sarcoma virus (SRC) and Syk tyrosine kinases, which does not inhibit JAK3, failed to improve the survival outcome of Min mice.

Thus, selective targeting of JAK3 was highly effective in preventing development of intestinal tumors in Min mice resulting in markedly improved survival outcomes. JAK3 inhibitors may therefore be useful in the prevention of colorectal cancer in individuals with FAP.

Key words

Adenomatous polyposis coli - CAS 202475-60-3 - Chemopreventive agents - Familial adenomatous polyposis - 4-(4'-Hydroxyphenyl) amino-6,7-dimethoxyquinazoline - JANEX-1, effects on intestinal tumors, mouse - Janus kinase 3 inhibitors - WHI-P131