Combination chemoprevention for colon cancer targeting polyamine synthesis and inflammation

Abstract

Increased polyamine synthesis and inflammation have long been associated with colon carcinogenesis in both preclinical models and in humans. Recent experimental studies suggest that polyamines may be mechanistically involved in colonic inflammatory processes. Genetic epidemiology results indicate that a single nucleotide polymorphism influencing the expression of a polyamine biosynthetic gene is associated with both risk of colon polyp occurrence and recurrence, and the response to aspirin as a polyp preventive agent. A prospective, randomized, placebo-controlled clinical trial of combination difluoromethylornithine, a selective inhibitor of polyamine synthesis, and sulindac, a nonsteroidal anti-inflammatory drug, found that the 3-year treatment was associated with a 70% reduction of recurrence of all adenomas, and over a 90% reduction of recurrence of advanced and/or multiple adenomas, without evidence of serious toxicities. This proof-of-principle trial indicates that targeting polyamine synthesis and inflammation can be an effective strategy for preventing the occurrence of the advanced and/or multiple adenomas that are most closely associated with the development of colon cancers in humans.

Fig. 1

(panel A) ODC expression is regulated by a number of signaling pathways. The APC tumor suppressor gene influences the expression of the MYC oncogene and the MYC antagonist MAD1(34). These E-box transcription factors, in turn, bind to consensus elements, including two E-boxes flanking a SNP which has functional consequences for transcription factor binding, to regulate ODC transcription (27). ODC expression is also regulated by the K-RAS oncogene (35). ODC converts ornithine to the diamine putrescine. This diamine is the precursor for the longer chain amines spermidine and spermine. Genetic and pharmacological evidence shows that this pathway is essential for normal growth, development, tissue repair and neoplasia (3). (panel B) The relationship between polyamine metabolism and inflammatory pathways in the colonic mucosa are depicted in this panel. Abbreviations include: ROS (reactive oxygen species), NO (nitric oxide), Arg (arginine), Orn (ornithine), Put (putrescine), COX (cyclooygenease), NOS (nitric oxide synthase), ODC (ornithine decarboxylase), SAT1 (spermidine/spermine N¹-acetyltransferase). Diamines, including putrescine, monoacetylspermidine and diacetylspermidine are exported by a common transporter (36), which was recently identified by us to including the solute carrier protein SLC3A2 (23). SLC3A2 partners with members of the Y+LAT family to form an arginine transporter. The roles of luminal factors, including polyamines and secondary bile acids, and stromal factors, such as prostaglandins, are shown. DFMO and sulindac lower polyamine contents in colonic epithelial cells by suppressing polyamine synthesis and activating polyamine catabolism and export. Sulindac also inhibits mucosal cyclooxygenases, which are predominately expressed in the colonic stroma prior to the formation of epithelial neoplasia.