Inflammation/infection has been implicated in the origin of 20-30% of epithelial cancers and, in many cases, occurs concurrently with increased production of reactive oxygen species (ROS). However, the precise pathways linking infection/inflammation to cancer are not well defined. Our data demonstrate that induction of the polyamine catabolic enzyme spermine oxidase (SMOX) by infection/inflammation produces DNA-damaging ROS and causes changes observed in carcinogenesis; inhibition of SMOX reduces the incidence of the observed carcinogenic changes. Importantly, we have compelling data indicating that the DNA damage induced by ROS leads to epigenetic transcriptional silencing. These data identify a molecular pathway in which infection/inflammation-induced SMOX activity is directly linked to carcinogenesis and define SMOX as an attractive target for chemoprevention. Selective inhibitors of SMOX would be of great value as probes to study inflammation/infection-induced carcinogenesis and would hold potential as chemopreventive agents, but, unfortunately, no such inhibitors exist. In light of these facts, the overall goals of this application are to identify and test selective inhibitors of SMOX that can serve as tool compounds and leads for the identification of chemopreventive agents. The following Specific Aims are designed to pursue these goals.
Aim 1. To identify inhibitors of SMOX using chemical synthesis of analogues, similarity searching, and structure-based design techniques. We will use multiple medicinal chemistry approaches to identify and synthesize potential inhibitors of SMOX, followed by hit-to-lead optimization of selected compounds with therapeutic potential.
Aim 2. To evaluate newly synthesized compounds for the ability to selectively inhibit SMOX and alter cellular response. The goal of this specific aim is to identify compounds that have selective inhibitory activity against SMOX with little or no inhibitory activity against closely related FAD-dependent amine oxidases, including the MAOs and LSD1. In this aim, we will determine the enzyme inhibitory kinetic profile for selected analogues, and we will determine the cellular effects of SMOX inhibition by these analogues in vitro.
Aim 3. To evaluate the effectiveness of SMOX inhibitors in vivo. As the primary purpose of this proposal is to identify effective and selective inhibitors of SMOX that have potential as chemopreventive agents, it is critical that they demonstrate effectiveness in a relevant carcinogenesis model. We will use our ETBF/Min mouse colon tumorigenesis model and a Mongolian gerbil model for H. pylori-induced gastric cancer, as we have previously published, to determine the in vivo anticancer effectiveness of newly identified SMOX inhibitors.

Public Health Relevance

Spermine oxidase (SMOX) induction in response to infection/inflammation is associated with the etiology of epithelial cancers. As such SMOX is an emerging target for chemoprevention for which no selective inhibitors exist. The goal of these studies is to identify effective SMOX inhibitors as leads for chemopreventive agents.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemo/Dietary Prevention Study Section (CDP)
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Perloff, Marjorie
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Kumarasinghe, Isuru R; Woster, Patrick M (2018) Cyclic peptide inhibitors of lysine-specific demethylase 1 with improved potency identified by alanine scanning mutagenesis. Eur J Med Chem 148:210-220
Cruz-Correa, Marcia; Hylind, Linda M; Marrero, Jessica Hernandez et al. (2018) Efficacy and Safety of Curcumin in Treatment of Intestinal Adenomas in Patients With Familial Adenomatous Polyposis. Gastroenterology 155:668-673
Gobert, Alain P; Al-Greene, Nicole T; Singh, Kshipra et al. (2018) Distinct Immunomodulatory Effects of Spermine Oxidase in Colitis Induced by Epithelial Injury or Infection. Front Immunol 9:1242
McKenna 3rd, James; Kapfhamer, David; Kinchen, Jason M et al. (2018) Metabolomic studies identify changes in transmethylation and polyamine metabolism in a brain-specific mouse model of tuberous sclerosis complex. Hum Mol Genet 27:2113-2124
Casero Jr, Robert A; Murray Stewart, Tracy; Pegg, Anthony E (2018) Polyamine metabolism and cancer: treatments, challenges andĀ opportunities. Nat Rev Cancer 18:681-695
Jain, V; Raina, S; Gheware, A P et al. (2018) Reduction in polyamine catabolism leads to spermine-mediated airway epithelial injury and induces asthma features. Allergy 73:2033-2045
Masuko, Takashi; Takao, Koichi; Samejima, Keijiro et al. (2018) N1-Nonyl-1,4-diaminobutane ameliorates brain infarction size in photochemically induced thrombosis model mice. Neurosci Lett 672:118-122
Murray Stewart, Tracy; Dunston, Tiffany T; Woster, Patrick M et al. (2018) Polyamine catabolism and oxidative damage. J Biol Chem 293:18736-18745
Casero Jr, Robert A (2018) Targeting the aryl hydrocarbon receptor/polyamine biosynthesis axis of evil for cancer therapy. J Clin Invest 128:4254-4256
Murray-Stewart, Tracy; Dunworth, Matthew; Foley, Jackson R et al. (2018) Polyamine Homeostasis in Snyder-Robinson Syndrome. Med Sci (Basel) 6:

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