Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer

Abstract

Edited by Eric R. Fearon Cancer is a set of diseases characterized by uncontrolled cell growth. In certain cancers of the gastrointestinal tract, the adenomatous polyposis coli (APC) tumor suppressor gene is altered in either germline or somatic cells and causes formation of risk factors, such as benign colonic or intestinal neoplasia, which can progress to invasive cancer. APC is a key component of the WNT pathway, contributing to normal GI tract development, and APC alteration results in dysregulation of the pathway for production of polyamines, which are ubiquitous cations essential for cell growth. Studies with mice have identified nonsteroidal anti-inflammatory drugs (NSAIDs) and difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, as potent inhibitors of colon carcinogenesis. Moreover, gene expression profiling has uncovered that NSAIDs activate polyamine catabolism and export. Several DFMO-NSAID combination strategies are effective and safe methods for reducing risk factors in clinical trials with patients having genetic or sporadic risk of colon cancer. These strategies affect cancer stem cells, inflammation, immune surveillance, and the microbiome. Pharmacotherapies consisting of drug combinations targeting the polyamine pathway provide a complementary approach to surgery and cytotoxic cancer treatments for treating patients with cancer risk factors. In this Minireview, we discuss the role of polyamines in colon cancer and highlight the mechanisms of select pharmacoprevention agents to delay or prevent carcinogenesis in humans.

Transcriptional and Metabolomic Analysis of L-Arginine/Nitric Oxide Pathway in Inflammatory Bowel Disease and Its Association with Local Inflammatory and Angiogenic Response: Preliminary Findings

“…ODC1 overexpression may increase susceptibility to neoplastic transformation as polyamines are involved in epigenetic regulation of gene expression by interacting with histone acetyltransferases, deacetylases, and demethylase and thus affecting chromatin state and global transcription [67]. Targeting ODC1 is currently being tested as a chemoprevention strategy in CRC, which, however, is associated with adenoma-carcinoma transformation [13][14][15] and not inflammation-induced carcinogenesis.…”

“…There is a growing interest in modulating the L-arginine/NO pathway as a chemopreventive strategy in CRC. Combination chemoprevention with ODC1 inhibitors has shown very promising results [13][14][15]. However, targeting ODC1 in IBD is controversial as polyamines are necessary for intestinal healing and gut health in general [16,17].…”

“…Therefore, the aim of this study is a comprehensive analysis of expression levels of key enzymes from the L-arginine/NO pathway in the context of the disease activity, local inflammatory and angiogenic response, and systemic concentrations of pathway metabolites in order to gain a better There is a growing interest in modulating the L-arginine/NO pathway as a chemopreventive strategy in CRC. Combination chemoprevention with ODC1 inhibitors has shown very promising results [13][14][15]. However, targeting ODC1 in IBD is controversial as polyamines are necessary for intestinal healing and gut health in general [16,17].…”

Colorectal cancer-associated anaerobic bacteria proliferate in tumor spheroids and alter the microenvironment

“…We also observed an increase in the polyamines N 1 -acetylspermidine and N 1 ,N 12 -diacetylspermine. Polyamines are important mediators in colon carcinogenesis, and polyamine metabolism has been a target of preclinical and clinical chemoprevention studies going back decades 50,51 . Interestingly, Johnson et al observed increased levels of polyamines in patient-derived colorectal tumors that were biofilm-positive (in comparison to biofilm-negative tumors), and hypothesized that these metabolites were being contributed by the biofilm community 42 .…”

Hydroxylamine Analogue of Agmatine: Magic Bullet for Arginine Decarboxylase

“…α-(Difluoromethyl)ornithine (DFMO) was synthesized in 1978 [13], and is the best-known and most widely used of the ODC inhibitors, serving for many years as the "gold standard inhibitor" of polyamine research [8,12]. DFMO is used as a drug to cure African sleeping sickness [14] and has also advanced in clinical trials with promising results as a cancer chemopreventive agent among populations with an elevated risk for specific epithelial cancers [15]. In addition, DFMO has fungicidal activity; this was demonstrated for the first time when it conferred protection on bean plants against infection by uredospores of the bean rust fungus Uromyces phaseoli Linnaeus in greenhouse experiments [16].…”