Polyamines as mediators of APC-dependent intestinal carcinogenesis and cancer chemoprevention

Abstract

Combination chemoprevention for cancer was proposed a quarter of a century ago, but has not been implemented in standard medical practice owing to limited efficacy and toxicity. Recent trials have targeted inflammation and polyamine biosynthesis, both of which are increased in carcinogenesis. Preclinical studies have demonstrated that DFMO (difluoromethylornithine), an irreversible inhibitor of ODC (ornithine decarboxylase) which is the first enzyme in polyamine biosynthesis, combined with NSAIDs (non-steroidal anti-inflammatory drugs) suppresses colorectal carcinogenesis in murine models. The preclinical rationale for combination chemoprevention with DFMO and the NSAID sulindac, was strengthened by the observation that a SNP (single nucleotide polymorphism) in the ODC promoter was prognostic for adenoma recurrence in patients with prior sporadic colon polyps and predicted reduced risk of adenoma in those patients taking aspirin. Recent results from a phase III clinical trial showed a dramatic reduction in metachronous adenoma number, size and grade. Combination chemoprevention with DFMO and sulindac was not associated with any serious toxicity. A non-significant trend in subclinical ototoxicity was detected by quantitative audiology in a subset of patients identified by a genetic marker. These preclinical, translational and clinical data provide compelling evidence for the efficacy of combination chemoprevention. DFMO and sulindac is a rational strategy for the prevention of metachronous adenomas, especially in patients with significant risk for colorectal cancer. Toxicities from this combination may be limited to subsets of patients identified by either past medical history or clinical tests.

Figure 1. The WNT pathway in normal and carcinogenic cells

The WNT pathway in a normal, adult, colonic epithelial cell is depicted on the left-hand side of the Figure. On the basolateral portion of the cell the WNT receptor is activated and transmits the signal intracellularly to the APC, GSK-3β and β-catenin complex. GSK-3β phosphorylates β-catenin, marking it for proteosomal degradation. The WNT pathway in carcinogenesis is depicted on the right-hand side of the Figure. The WNT receptor may be activated and transmission of the signal intracellularly may occur, but inactivation of β-catenin by GSK-3β does not. Cytoplasmic accumulation of β-catenin leads to its nuclear translocation and binding with its cognate partner TCF/LEF. This heterodimerization regulates genes through transcription, notably of MYC.

Figure 2. ODC regulation occurs through both positive and negative mechanisms

ODC is suppressed by MAD. Transcriptional activation of ODC can occur through MYC, RAS or both. Upstream activation of c-myc may occur via mutant APC. Pharmacogenetic manipulation of ODC occurs through identification of SNP status. The combination of these factors may increase individual risk stratification.

Figure 3. Polyamine transport is shown schematically via import, export, anabolism and catabolism

Arginine is imported into the cell and then converted into ornithine which contributes to the polyamine pools. Polyamine pools may be further increased by import or decreased by catabolism and export.

Figure 4. Inflammation within a colonic epithelial cell may occur through multiple mechanisms

Imported dietary arginine may either be converted into NO or processed in the polyamine pathway. NSAIDs can disrupt these and other pathways via inhibition of NOS-2, up-regulation of polyamine export or inhibition of COX-2. External sources of polyamines and bile acids may also contribute to inflammation.

Figure 5. The interaction among mutant-APC, polyamines and inflammation is depicted in a colonic epithelial cell

Mutant-APC and activated K-RAS lead to increased MYC production and up-regulate ODC which increases the polyamine concentration. Elevated dietary arginine can also contribute to increased polyamine pools. NSAIDs and DFMO can inhibit multiple targets in both the polyamine and inflammatory pathways.