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• W2898431520 abstract "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. 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. Polyamines were described as early as the late 17th century with their discovery credited to Van Leeuwenhoek as discussed in Ref. 1Tabor C.W. Tabor H. It all started on a streetcar in Boston.Annu. Rev. Biochem. 1999; 68 (10872442): 1-3210.1146/annurev.biochem.68.1.1Crossref PubMed Scopus (20) Google Scholar. Their importance as targets for cancer treatment has only become apparent since the 1960s, as highlighted in the timeline shown in Fig. 1. In several seminal papers, Dykstra and Herbst (2Dykstra Jr., W.G. Herbst E.J. Spermidine in regenerating liver: relation to rapid synthesis of ribonucleic acid.Science. 1965; 149 (17809408): 428-42910.1126/science.149.3682.428Crossref PubMed Scopus (135) Google Scholar) and Raina et al. (3Raina A. Jänne J. Siimes M. Stimulation of polyamine synthesis in relation to nucleic acids in regenerating rat liver.Biochim. Biophys. Acta. 1966; 123 (5964040): 197-20110.1016/0005-2787(66)90173-0Crossref PubMed Scopus (134) Google Scholar) reported strong associations between concentrations of specific polyamines and tissue growth in rodents. Russell and Snyder (4Russell D. Snyder S.H. Amine synthesis in rapidly growing tissues: ornithine decarboxylase activity in regenerating rat liver, chick embryo, and various tumors.Proc. Natl. Acad. Sci. U.S.A. 1968; 60 (4299947): 1420-142710.1073/pnas.60.4.1420Crossref PubMed Scopus (883) Google Scholar) extended these original findings to other species and tumor models. In addition, they demonstrated that the activity of ornithine decarboxylase 1 (ODC1) was rapidly induced by growth stimuli. They also found that the enzyme had an exceedingly short half-life (∼10 min), suggesting that ODC1 was under strict regulatory control. By the mid-1970s, O’Brien et al. (5O'Brien T.G. Simsiman R.C. Boutwell R.K. Induction of the polyamine-biosynthetic enzymes in mouse epidermis by tumor-promoting agents.Cancer Res. 1975; 35 (48421): 1662-1670PubMed Google Scholar) showed that a variety of tumor promoters of different classes had similar abilities to induce both ODC1 enzyme activity and skin tumor formation. These reports were all important original findings but did not provide evidence of cause–effect relationships between polyamines and growth. Herbert Tabor, for whom this issue of minireviews is dedicated on the anniversary of his 100th birth year, and colleagues at the National Institutes of Health used genetic methods to address the question of causality. They established that polyamines were not essential for growth of bacteria in general (6Hafner E.W. Tabor C.W. Tabor H. Mutants of Escherichia coli that do not contain 1,4-diaminobutane (putrescine) or spermidine.J. Biol. Chem. 1979; 254 (159306): 12419-12426Abstract Full Text PDF PubMed Google Scholar, 7Tabor H. Hafner E.W. Tabor C.W. Construction of an Escherichia coli strain unable to synthesize putrescine, spermidine, or cadaverine: characterization of two genes controlling lysine decarboxylase.J. Bacteriol. 1980; 144 (7002915): 952-956Crossref PubMed Google Scholar), but the lack of enzymes to produce polyamines did compromise bacterial growth under conditions that suggested polyamines were acting by a mechanism affecting protein translation (8Tabor H. Tabor C.W. Cohn M.S. Hafner E.W. Streptomycin resistance (rpsL) produces an absolute requirement for polyamines for growth of an Escherichia coli strain unable to synthesize putrescine and spermidine [Δ(speA-speB)ΔspecC].J. Bacteriol. 1981; 147 (7021537): 702-704Crossref PubMed Google Scholar). In collaboration with his wife Celia, Herbert Tabor showed that polyamines were essential for growth in specific strains of yeast (9Tabor C.W. Tabor H. Polyamines.Annu. Rev. Biochem. 1984; 53 (6206782): 749-79010.1146/annurev.bi.53.070184.003533Crossref PubMed Scopus (3230) Google Scholar, 10Tabor C.W. Tabor H. Tyagi A.K. Cohn M.S. The biochemistry, genetics, and regulation of polyamine biosynthesis in Saccharomyces cerevisiae.Fed. Proc. 1982; 41 (6754461): 3084-3088PubMed Google Scholar). In this same time frame, Metcalf et al. (11Metcalf B.W. Bey P. Danzin C. Jung M.J. Cagara P. Ververt J.P. Catalytic irreversible inhibition of mammalian ornithine decarboxylase (E.C. 4.1.1.17) by substrate and product analogues.J. Am. Chem. Soc. 1978; 100 (PMID not found): 2551-255310.1021/ja00476a050Crossref Scopus (979) Google Scholar) at the Merrell Research Institute in Strasbourg, France (known by its French name Centre de Recherche Merrell International-CRMI), reported the synthesis of difluoromethylornithine (DFMO), 2The abbreviations used are: DFMOdifluoromethylornithineAPCadenomatous polyposis coliGIgastrointestinalNSAIDnonsteroidal anti-inflammatory drugFAPfamilial adenomatous polyposisIENintraepithelial neoplasiaCRCcolorectal cancerCRAcolorectal adenomaOAZornithine decarboxylase inhibitory protein antizymeTGFβtransforming growth factor βPPARγperoxisomal proliferator-activated receptor γPTIpolyamine transport inhibitorESCembryonic stem cellMTAP5′-methylthioadenosine phosphorylaseNETneutrophil extracellular trapODCornithine decarboxylase. a highly targeted drug whose mechanism involved enzyme activation and irreversible inhibition of ODC1, in 1978. Scientists at CRMI quickly reported the growth inhibitory and anti-tumor effects of DFMO and other ODC1 inhibitors (12Mamont P.S. Duchesne M.C. Grove J. Bey P. Anti-proliferative properties of dl-α-difluoromethyl ornithine in cultured cells. A consequence of the irreversible inhibition of ornithine decarboxylase.Biochem. Biophys. Res. Commun. 1978; 81 (656104): 58-6610.1016/0006-291X(78)91630-3Crossref PubMed Scopus (371) Google Scholar, 13Prakash N.J. Schechter P.J. Mamont P.S. Grove J. Koch-Weser J. Sjoerdsma A. Inhibition of EMT6 tumor growth by interference with polyamine biosynthesis; effects of α-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase.Life Sci. 1980; 26 (7360002): 181-19410.1016/0024-3205(80)90292-1Crossref PubMed Scopus (118) Google Scholar14Bartholeyns J. Mamont P. Casara P. Antitumor properties of (2R,5R)-6-heptyne-2,5-diamine, a new potent enzyme-activated irreversible inhibitor of ornithine decarboxylase, in rodents.Cancer Res. 1984; 44 (6435861): 4972-4977PubMed Google Scholar). These early investigations found that the profound growth inhibitory effects of DFMO were not accompanied by cytotoxicity. Slaga and co-workers (15Weeks C.E. Herrmann A.L. Nelson F.R. Slaga T.J. α-Difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin.Proc. Natl. Acad. Sci. U.S.A. 1982; 79 (6821130): 6028-603210.1073/pnas.79.19.6028Crossref PubMed Scopus (181) Google Scholar) used DFMO to show that inhibition of polyamine synthesis could inhibit skin carcinogenesis in mouse models and that the effect of the drug was on specific features of tumor promotion. Kingsnorth et al. (16Kingsnorth A.N. King W.W. Diekema K.A. McCann P.P. Ross J.S. Malt R.A. Inhibition of ornithine decarboxylase with 2-difluoromethylornithine: reduced incidence of dimethylhydrazine-induced colon tumors in mice.Cancer Res. 1983; 43 (6406047): 2545-2549PubMed Google Scholar) were the first group to show DFMO inhibited colon carcinogenesis in a rodent model of colon carcinogenesis, the dimethylhydrazine-treated rat. difluoromethylornithine adenomatous polyposis coli gastrointestinal nonsteroidal anti-inflammatory drug familial adenomatous polyposis intraepithelial neoplasia colorectal cancer colorectal adenoma ornithine decarboxylase inhibitory protein antizyme transforming growth factor β peroxisomal proliferator-activated receptor γ polyamine transport inhibitor embryonic stem cell 5′-methylthioadenosine phosphorylase neutrophil extracellular trap ornithine decarboxylase. Clinical trials of high-dose intravenous DFMO as a therapy for advanced cancers were conducted in the 1980s and were generally negative from both a safety and efficacy perspective (17Von Hoff D.D. There are no bad anticancer agents, only bad clinical trial designs–twenty-first Richard and Hinda Rosenthal Foundation Award Lecture.Clin. Cancer Res. 1998; 4 (9607564): 1079-1086PubMed Google Scholar). Clinical trials in patients with conditions other than cancer were also conducted, and these trials led to regulatory approval of high-dose DFMO administered intravenously for treatment of patients with a form of African Sleeping Sickness in 1990 (18Nightingale S.L. From the food and drug administration.JAMA. 1991; 265 (1995961)122910.1001/jama.1991.03460100029008Crossref PubMed Scopus (5) Google Scholar) and a topical form of DFMO for female hirsutism in 2000 (19Balfour J.A. McClellan K. Topical eflornithine.Am. J. Clin. Dermatol. 2001; 2 (11705097): 197-201Crossref PubMed Scopus (109) Google Scholar). Achieving regulatory approval of an oral dosage form of DFMO has never been accomplished for any medical indication and is a current major challenge for development of this and related drugs to treat cancer risk factors. A major motivation for the work described in this Minireview was identification of risk factors for leading causes of disease and death in the United States and the understanding that some of these factors are associated with the risk of cancer (20Mokdad A.H. Ballestros K. Echko M. Glenn S. Olsen H.E. Mullany E. Lee A. Khan A.R. Ahmadi A. Ferrari A.J. Kasaeian A. Werdecker A. Carter A. Zipkin B. et al.US Burden of Disease CollaboratorsThe State of US Health, 1990–2016: Burden of diseases, injuries, and risk factors among US states.JAMA. 2018; 319 (29634829): 1444-147210.1001/jama.2018.0158Crossref PubMed Scopus (717) Google Scholar). Many common risk factors, such as diet, tobacco use, high body-mass index, air pollution, and low physical activity, are not amenable to interventions with pharmacotherapies. However, some cancer-specific risk factors can be managed by pharmacotherapies to reduce risk of disease and mortality analogous to targeting high cholesterol in patients with a risk of cardiovascular disease using pharmacoprevention strategies (e.g. statins) (21Ford E.S. Ajani U.A. Croft J.B. Critchley J.A. Labarthe D.R. Kottke T.E. Giles W.H. Capewell S. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000.N. Engl. J. Med. 2007; 356 (17554120): 2388-239810.1056/NEJMsa053935Crossref PubMed Scopus (2160) Google Scholar). Cancer-specific risk factors that could be targets for pharmacoprevention strategies include intraepithelial neoplasia (IEN) (22O'Shaughnessy J.A. Kelloff G.J. Gordon G.B. Dannenberg A.J. Hong W.K. Fabian C.J. Sigman C.C. Bertagnolli M.M. Stratton S.P. Lam S. Nelson W.G. Meyskens F.L. Alberts D.S. Follen M. Rustgi A.K. et al.Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development.Clin. Cancer Res. 2002; 8 (11839647): 314-346PubMed Google Scholar). Colorectal adenomas (CRA) are an example of an IEN risk factor for colorectal cancer (CRC). Failure to remove CRAs is associated with an increase in CRC in humans (23Winawer S.J. Zauber A.G. Ho M.N. O'Brien M.J. Gottlieb L.S. Sternberg S.S. Waye J.D. Schapiro M. Bond J.H. Panish J.F. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup.N. Engl. J. Med. 1993; 329 (8247072): 1977-198110.1056/NEJM199312303292701Crossref PubMed Scopus (3899) Google Scholar). More recent studies indicate that screening for CRAs, which is associated with the removal of large/advanced CRAs, is strongly associated with a reduction in mortality (24Baxter N.N. Goldwasser M.A. Paszat L.F. Saskin R. Urbach D.R. Rabeneck L. Association of colonoscopy and death from colorectal cancer.Ann. Intern. Med. 2009; 150 (19075198): 1-810.7326/0003-4819-150-1-200901060-00306Crossref PubMed Scopus (1057) Google Scholar). A significant challenge in the field of oncology is to determine whether managing cancer risk factors, such as CRAs, with pharmacotherapies can prevent or delay cancer and reduce cancer disease burden and deaths. The major goal of the work summarized in this Minireview was to understand the mechanistic basis of pharmacoprevention agents and determine whether intervening in the polyamine pathway could be used successfully to delay/prevent carcinogenesis in humans. Following the earlier observations of the association of polyamines and growth, Luk et al. (25Lux G.D. Marton L.J. Baylin S.B. Ornithine decarboxylase is important in intestinal mucosal maturation and recovery from injury in rats.Science. 1980; 210 (6774420): 195-19810.1126/science.6774420Crossref PubMed Scopus (320) Google Scholar) took advantage of the new inhibitor of this pathway, DFMO, to address the importance of polyamines in gut development in rodent models. They reported that DFMO could delay gut development in fetal rats and recovery from chemotherapy-induced gut injury in adult rats (25Lux G.D. Marton L.J. Baylin S.B. Ornithine decarboxylase is important in intestinal mucosal maturation and recovery from injury in rats.Science. 1980; 210 (6774420): 195-19810.1126/science.6774420Crossref PubMed Scopus (320) Google Scholar). This finding led Luk et al. (25Lux G.D. Marton L.J. Baylin S.B. Ornithine decarboxylase is important in intestinal mucosal maturation and recovery from injury in rats.Science. 1980; 210 (6774420): 195-19810.1126/science.6774420Crossref PubMed Scopus (320) Google Scholar) to ask whether the expression of ODC1 and polyamines, which appeared to be important in normal gut mucosal development, was altered in the apparently normal gut mucosa of patients with familial adenomatous polyposis (FAP), a genetic syndrome associated with near 100% risk of development of colon cancer. They discovered that both ODC1 and polyamines are elevated in the apparently normal colonic mucosa of FAP patients and appeared to identify genotypic individuals (26Luk G.D. Baylin S.B. Ornithine decarboxylase as a biologic marker in familial colonic polyposis.N. Engl. J. Med. 1984; 311 (6738598): 80-8310.1056/NEJM198407123110202Crossref PubMed Scopus (251) Google Scholar). Following the identification of the APC gene in humans (27Groden J. Thliveris A. Samowitz W. Carlson M. Gelbert L. Albertsen H. Joslyn G. Stevens J. Spirio L. Robertson M. Identification and characterization of the familial adenomatous polyposis coli gene.Cell. 1991; 66 (1651174): 589-60010.1016/0092-8674(81)90021-0Abstract Full Text PDF PubMed Scopus (2399) Google Scholar), the elevation of ODC1 enzyme activity and polyamine contents in apparently normal colonic mucosa of genotypic FAP patients was established (28Giardiello F.M. Hamilton S.R. Hylind L.M. Yang V.W. Tamez P. Casero Jr., R.A. Ornithine decarboxylase and polyamines in familial adenomatous polyposis.Cancer Res. 1997; 57 (9000553): 199-201PubMed Google Scholar). Fig. 2 depicts the signaling of ODC1 and the polyamine pathway in patients with FAP and in normal individuals. This depiction is based on studies in humans and mouse models. Multiple intestinal neoplasia in the ApcMin/+ mouse model of FAP is caused by a mutation in the murine homolog of the human APC gene (29Su L.K. Kinzler K.W. Vogelstein B. Preisinger A.C. Moser A.R. Luongo C. Gould K.A. Dove W.F. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene.Science. 1992; 256 (1350108): 668-67010.1126/science.1350108Crossref PubMed Scopus (1346) Google Scholar). Expression of ODC1 and other genes in the polyamine pathway, including the gene encoding the ornithine decarboxylase inhibitory protein antizyme (OAZ), are influenced by the mutant APC-encoding gene in the mouse model (30Erdman S.H. Ignatenko N.A. Powell M.B. Blohm-Mangone K.A. Holubec H. Guillén-Rodriguez J.M. Gerner E.W. APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse.Carcinogenesis. 1999; 20 (10469614): 1709-171310.1093/carcin/20.9.1709Crossref PubMed Scopus (79) Google Scholar). ODC1 RNA levels were increased in both intestinal and colonic mucosa, whereas OAZ RNA levels are decreased especially in the intestinal mucosa of these mice. Mechanistic studies in human cells support the pathway depiction shown in Fig. 2. He et al. (31He T.C. Sparks A.B. Rago C. Hermeking H. Zawel L. da Costa L.T. Morin P.J. Vogelstein B. Kinzler K.W. Identification of c-MYC as a target of the APC pathway.Science. 1998; 281 (9727977): 1509-151210.1126/science.281.5382.1509Crossref PubMed Scopus (4075) Google Scholar) showed that c-MYC is transcriptionally activated by the APC signaling pathway, and ODC1 was known to be a transcriptional target of c-MYC (32Bello-Fernandez C. Packham G. Cleveland J.L. The ornithine decarboxylase gene is a transcriptional target of c-Myc.Proc. Natl. Acad. Sci. U.S.A. 1993; 90 (8356088): 7804-780810.1073/pnas.90.16.7804Crossref PubMed Scopus (663) Google Scholar). Conditional expression of WT APC in human colon cancer cells containing mutant APC demonstrated that WT APC was restrictive for ODC1 expression (33Fultz K.E. Gerner E.W. APC-dependent regulation of ornithine decarboxylase in human colon tumor cells.Mol. Carcinog. 2002; 34 (12112318): 10-1810.1002/mc.10043Crossref PubMed Scopus (40) Google Scholar). This suppression depended on the presence of canonical MYC-binding sites in the ODC1 promoter. Tissue-specific knockdown of c-MYC in ApcMin/+ mice established that MYC was involved in APC-dependent intestinal and colonic carcinogenesis (34Ignatenko N.A. Holubec H. Besselsen D.G. Blohm-Mangone K.A. Padilla-Torres J.L. Nagle R.B. de Alboránç I.M. Guillen-R. J.M. Gerner E.W. Role of c-Myc in intestinal tumorigenesis of the ApcMin/+ mouse.Cancer Biol. Ther. 2006; 5 (17106247): 1658-166410.4161/cbt.5.12.3376Crossref PubMed Scopus (39) Google Scholar) and that treatment of ApcMin/+ mice with DFMO reduced both intestinal and colonic carcinogenesis (30Erdman S.H. Ignatenko N.A. Powell M.B. Blohm-Mangone K.A. Holubec H. Guillén-Rodriguez J.M. Gerner E.W. APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse.Carcinogenesis. 1999; 20 (10469614): 1709-171310.1093/carcin/20.9.1709Crossref PubMed Scopus (79) Google Scholar, 35Yerushalmi H.F. Besselsen D.G. Ignatenko N.A. Blohm-Mangone K.A. Padilla-Torres J.L. Stringer D.E. Guillen J.M. Holubec H. Payne C.M. Gerner E.W. Role of polyamines in arginine-dependent colon carcinogenesis in Apc(Min) (/+) mice.Mol. Carcinog. 2006; 45 (16705737): 764-77310.1002/mc.20246Crossref PubMed Scopus (40) Google Scholar). Polyamines may be involved in colon carcinogenesis due to disruption in pathways other than the APC/MYC pathway. Green and Hudson (36Green J.E. Hudson T. The promise of genetically engineered mice for cancer prevention studies.Nat. Rev. Cancer. 2005; 5 (15738982): 184-19810.1038/nrc1565Crossref PubMed Scopus (63) Google Scholar) have reviewed the roles of several signaling pathways implicated in the development of colon cancers. KRAS-dependent tumorigenesis is inhibited by DFMO in human Caco-2 xenografts (37Ignatenko N.A. Zhang H. Watts G.S. Skovan B.A. Stringer D.E. Gerner E.W. The chemopreventive agent α-difluoromethylornithine blocks Ki-ras-dependent tumor formation and specific gene expression in Caco-2 cells.Mol. Carcinog. 2004; 39 (15057874): 221-23310.1002/mc.20008Crossref PubMed Scopus (42) Google Scholar), and colon carcinogenesis in transforming growth factor β (TGFβ)–deficient mice is associated with changes in the polyamine and other metabolic pathways in the gut microbiome of these mice (38Daniel S.G. Ball C.L. Besselsen D.G. Doetschman T. Hurwitz B.L. Functional changes in the gut microbiome contribute to transforming growth factor β-deficient colon cancer.mSystems. 2017; 2 (28951889): e00017-e00065Crossref Scopus (41) Google Scholar). The role of the microbiome will be discussed further in a subsequent section of this Minireview. DFMO was an effective but incomplete inhibitor of experimental carcinogenesis in the ApcMin/+ mouse (30Erdman S.H. Ignatenko N.A. Powell M.B. Blohm-Mangone K.A. Holubec H. Guillén-Rodriguez J.M. Gerner E.W. APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse.Carcinogenesis. 1999; 20 (10469614): 1709-171310.1093/carcin/20.9.1709Crossref PubMed Scopus (79) Google Scholar) and other models (39Meyskens Jr., F.L. Gerner E.W. Development of difluoromethylornithine (DFMO) as a chemoprevention agent.Clin. Cancer Res. 1999; 5 (10353725): 945-951PubMed Google Scholar). Sporn (40Sporn M.B. Combination chemoprevention of cancer.Nature. 1980; 287 (7432445): 107-10810.1038/287107a0Crossref PubMed Scopus (65) Google Scholar) was an early advocate for using combinations of agents as a means to increase efficacy and reduce toxicity of treatments to suppress carcinogenesis. The nonsteroidal anti-inflammatory drug (NSAID) sulindac reduced colonic and rectal polyps in patients with FAP in a statistically significant but incomplete manner in a randomized placebo-controlled trial (41Giardiello F.M. Hamilton S.R. Krush A.J. Piantadosi S. Hylind L.M. Celano P. Booker S.V. Robinson C.R. Offerhaus G.J. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis.N. Engl. J. Med. 1993; 328 (8385741): 1313-131610.1056/NEJM199305063281805Crossref PubMed Scopus (1552) Google Scholar). The efficacy of combinations of DFMO with other NSAIDs, including paroxysm (42Nigro N.D. Bull A.W. Boyd M.E. Inhibition of intestinal carcinogenesis in rats: effect of difluoromethylornithine with piroxicam or fish oil.J. Natl. Cancer Inst. 1986; 77 (3099048): 1309-1313PubMed Google Scholar), indomethacin (43Abou-el-Ela S.H. Prasse K.W. Farrell R.L. Carroll R.W. Wade A.E. Bunce O.R. Effects of dl-2-difluoromethylornithine and indomethacin on mammary tumor promotion in rats fed high n-3 and/or n-6 fat diets.Cancer Res. 1989; 49 (2538226): 1434-1440PubMed Google Scholar), and aspirin (44Li H. Schut H.A. Conran P. Kramer P.M. Lubet R.A. Steele V.E. Hawk E.E. Kelloff G.J. Pereira M.A. Prevention by aspirin and its combination with α-difluoromethylornithine of azoxymethane-induced tumors, aberrant crypt foci and prostaglandin E2 levels in rat colon.Carcinogenesis. 1999; 20 (10190557): 425-43010.1093/carcin/20.3.425Crossref PubMed Scopus (87) Google Scholar), was reported for several models of experimental carcinogenesis. The precise mechanism by which NSAIDs inhibit carcinogenesis remains elusive. Whereas NSAIDs are generally considered to work via their effects on cyclooxygenases and prostaglandin metabolism, noncyclooxygenase mechanisms have been reported (45Gurpinar E. Grizzle W.E. Piazza G.A. COX-independent mechanisms of cancer chemoprevention by anti-inflammatory drugs.Front. Oncol. 2013; 3 (23875171): 181Crossref PubMed Scopus (93) Google Scholar). Indomethacin suppresses the tumor-promoter induction of ODC1 in experimental skin carcinogenesis (46Verma A.K. Ashendel C.L. Boutwell R.K. Inhibition by prostaglandin synthesis inhibitors of the induction of epidermal ornithine decarboxylase activity, the accumulation of prostaglandins, and tumor promotion caused by 12-O-tetradecanoylphorbol-13-acetate.Cancer Res. 1980; 40 (6243250): 308-315PubMed Google Scholar). To understand potential mechanisms of action of sulindac, patterns of gene expression resulting from treatment with sulindac sulfone, a sulindac metabolite lacking cyclooxygenase inhibitory activity, were measured in human colon tumor-derived cells (47Babbar N. Ignatenko N.A. Casero Jr, R.A. Gerner E.W. Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer.J. Biol. Chem. 2003; 278 (14506281): 47762-4777510.1074/jbc.M307265200Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). Sulindac sulfone inhibited cell growth and induced apoptosis and the expression of the spermidine/spermine N-acetyltransferase (SAT1), a polyamine catabolic gene product implicated in polyamine export (48Xie X. Gillies R.J. Gerner E.W. Characterization of a diamine exporter in Chinese hamster ovary cells and identification of specific polyamine substrates.J. Biol. Chem. 1997; 272 (9252359): 20484-2048910.1074/jbc.272.33.20484Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). The sulindac sulfone induction of SAT1 gene expression was shown to occur via the cyclooxygenase-independent transcriptional activation of SAT1 by a peroxisomal proliferator-activated receptor γ (PPARγ)–dependent mechanism acting at a specific PPARγ-responsive element in the SAT1 gene. Treatment of cells with sulindac sulfone induces SAT1 and stimulates polyamine export. Other NSAIDs also induce SAT1, and presumably polyamine export, but by unique mechanisms (49Babbar N. Gerner E.W. Casero Jr., R.A. Induction of spermidine/spermine N1-acetyltransferase (SSAT) by aspirin in Caco-2 colon cancer cells.Biochem. J. 2006; 394 (16262603): 317-32410.1042/BJ20051298Crossref PubMed Scopus (83) Google Scholar). These results led us to hypothesize that combinations of DFMO and NSAIDs, such as sulindac, might be working via complementary mechanisms (depicted in Fig. 3) to suppress dysregulated and high levels of polyamines in neoplasia by inhibiting both polyamine synthesis and stimulating polyamine catabolism and export (50Gerner E.W. Meyskens Jr., F.L. Polyamines and cancer: old molecules, new understanding.Nat. Rev. Cancer. 2004; 4 (15510159): 781-79210.1038/nrc1454Crossref PubMed Scopus (881) Google Scholar). Experimental studies in the ApcMin/+ mouse supported this hypothesis (DFMO and sulindac combination in cancer chemoprevention; United States patent no. 6,258,845, 2001) (51Ignatenko N.A. Besselsen D.G. Stringer D.E. Blohm-Mangone K.A. Cui H. Gerner E.W. Combination chemoprevention of intestinal carcinogenesis in a murine model of familial adenomatous polyposis.Nutr. Cancer. 2008; 60 (19003578): 30-3510.1080/01635580802401317Crossref PubMed Scopus (31) Google Scholar). A clinical trial of DFMO and sulindac in patients with sporadic risk of colorectal cancer showed dramatic efficacy to reduce both metachronous colorectal adenomas (52Meyskens F.L. McLaren C.E. Pelot D. Fujikawa-Brooks S. Carpenter P.M. Hawk E. Kelloff G. Lawson M.J. Kidao J. McCracken J. Albers C.G. Ahnen D.J. Turgeon D.K. Goldschmid S. Lance P. et al.Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo controlled, double-blind trial.Cancer Prev. Res. 2008; 1: 32-3810.1158/1940-6207.CAPR-08-0042Crossref PubMed Scopus (411) Google Scholar) and rectal mucosal polyamine but not prostaglandin E2 contents (53Thompson P.A. Wertheim B.C. Zell J.A. Chen" @default.
• W2898431520 created "2018-11-02" @default.
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• W2898431520 creator A5052134778 @default.
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• W2898431520 date "2018-11-01" @default.
• W2898431520 modified "2023-10-07" @default.
• W2898431520 title "Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer" @default.
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