Levels of Rectal Mucosal Polyamines and Prostaglandin E2 Predict Ability of DFMO and Sulindac to Prevent Colorectal Adenoma

Thompson, Patricia A.; Wertheim, Betsy C.; Zell, Jason A.; Chen, Wen-Pin; McLaren, Christine E.; LaFleur, Bonnie; Meyskens, Frank L.; Gerner, Eugene W.

doi:10.1053/j.gastro.2010.06.005

Cited by 49 publications

(38 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While various TRPC channels conduct dynamic physiological functions, one of the most prominent cases is the role of TRPC4 and TRPC6 in gastrointestinal (GI) physiology, especially in ileum myocytes [16,30,36]. Muscarinic cationic current (mI cat) , a cationic current evoked by muscarinic stimulation, in murine ileal myocyte had been heavily studied to identify its molecular candidates.…”

Section: Introductionmentioning

confidence: 99%

Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids

Kim

Moon

Shin

et al. 2015

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Transient receptor potential canonical (TRPC) 4 channels are calcium-permeable, nonselective cation channels and are widely expressed in mammalian tissue, especially in the GI tract and brain. TRPC4 channels are known to be involved in neurogenic contraction of ileal smooth muscle cells via generating cationic current after muscarinic stimulation (muscarinic cationic current (mIcat)). Polyamines exist in numerous tissues and are believed to be involved in cell proliferation, differentiation, scar formation, wound healing, and carcinogenesis. Besides, physiological polyamines are essential to maintain inward rectification of cardiac potassium channels (Kir2.1). At membrane potentials more positive than equilibrium potential, intracellular polyamines plug the cytosolic surface of the Kir2.1 so that potassium ions cannot pass through the pore. Recently, it was reported that polyamines inhibit not only cardiac potassium channels but also nonselective cation channels that mediate the generation of mIcat. Here, we report that TRPC4, a definite mIcat mediator, is inhibited by intracellular spermine with great extent. The inhibition was specific to TRPC4 and TRPC5 channels but was not effective to TRPC1/4, TRPC1/5, and TRPC3 channels. For this inhibition to occur, we found that glutamates at 728th and 729th position of TRPC4 channels are essential whereby we conclude that spermine blocks the TRPC4 channel with electrostatic interaction between negative amino acids at the C-terminus of the channel.

show abstract

Section: Introductionmentioning

confidence: 99%

Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids

Kim

Moon

Shin

et al. 2015

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

show abstract

“…Although this analysis is limited because of the small number of patients and that fact that most had stable findings at pathology, it nevertheless suggests a potential association between polyamine suppression and treatment response. In patients treated with DFMO and the NSAID sulindac for colon cancer chemoprevention, the data suggest that efficacy was greatest in subjects with low spermidine/spermine ratios at baseline, although polyamine modulation did not correlate with efficacy (46). DFMO, at a dose of 0.5 g/m 2 /d, was well tolerated and toxicities were limited to fatigue, insomnia, or chest pain that were mild (grade 1 or 2) and whose attributions were regarded as unlikely to be related to the study drug.…”

Section: Discussionmentioning

confidence: 90%

“…Putrescine is the most prevalent dietary polyamine (44) and is the preferred substrate for the polyamine transport system (45). A study in patients with prior colorectal adenomas found that putrescine levels rebounded in normal rectal mucosa after 12 months of continuous low-dose DMFO (500 mg/d), suggesting an adaptive response to prolonged ODC suppression with a compensatory cellular uptake of diet-or bacteria-derived putrescine (46).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Difluoromethylornithine for the Chemoprevention of Barrett's Esophagus and Mucosal Dysplasia

Sinicrope

Broaddus

Joshi

et al. 2011

Cancer Prevention Research

View full text Add to dashboard Cite

Patients with Barrett's esophagus (BE) and dysplasia are candidates for chemopreventive strategies to reduce cancer risk. We determined the effects of difluoromethylornithine (DMFO) on mucosal polyamines, gene expression, and histopathology in BE. Ten patients with BE and low-grade dysplasia participated in a single-arm study of DFMO (0.5 g/m 2 /d) given continuously for 6 months. Esophagoscopy with biopsies was conducted at baseline, 3, 6, and 12 months. Dysplasia was graded by a gastrointestinal pathologist. Audiology was assessed (at baseline and at 6 months). Mucosal polyamines were measured by high-performance liquid chromatography. Microarray-based gene expression was analyzed using a cDNA two-color chip. DFMO suppressed levels of the polyamines putrescine (P ¼ 0.02) and spermidine (P ¼ 0.02) and the spermidine/spermine ratio (P < 0.01) in dysplastic BE (6 months vs. baseline) that persisted at 6 months following drug cessation. Among the top 25 modulated genes, we found those regulating p53-mediated cell signaling (RPL11), cell-cycle regulation (cyclin E2), and cell adhesion and invasion (Plexin1). DFMO downregulated Kr€ uppellike factor 5 (KLF5), a transcription factor promoting cell proliferation, and suppressed RFC5 whose protein interacts with proliferating cell nuclear antigen. Histopathology showed regression of dysplasia (n ¼ 1), stable disease (n ¼ 8), and progression to high-grade dysplasia (n ¼ 1). Polyamines were suppressed in the responder to a greater extent than in stable cases. DFMO was well tolerated, and one patient had subclinical, unilateral ototoxicity. DFMO suppressed mucosal polyamines and modulated genes that may be mechanistically related to its chemopreventive effect. Further study of DFMO for the chemoprevention of esophageal cancer in BE patients is warranted.

show abstract

“…Polyamines cause cell proliferation through regulation of gene expression, and elevated levels of both ODC and polyamines are associated with epithelial cancers (4). Mouse models of skin carcinogenesis have demonstrated that ODC is induced by ultraviolet light and chemical carcinogens (3).…”

Section: Introductionmentioning

confidence: 99%

Phase IIB Randomized Study of Topical Difluoromethylornithine and Topical Diclofenac on Sun-Damaged Skin of the Forearm

Jeter

Curiel‐Lewandrowski

Stratton

et al. 2016

Cancer Prevention Research

View full text Add to dashboard Cite

Prevention of nonmelanoma skin cancers remains a health priority due to high costs associated with this disease. Diclofenac and difluoromethylornithine (DFMO) have demonstrated chemopreventative efficacy for cutaneous squamous cell carcinomas. We designed a randomized study of the combination of DFMO and diclofenac in the treatment of sun-damaged skin. Individuals with visible cutaneous sun damage were eligible. Subjects were randomized to one of three groups: topical DFMO applied twice daily, topical diclofenac applied daily, or DFMO plus diclofenac. The treatment was limited to an area on the left forearm, and the duration of use was 90 days. We hypothesized that combination therapy would have increased efficacy compared to single-agent therapy. The primary outcome was change in karyometric average nuclear abnormality (ANA) in the treated skin. Individuals assessing the biomarkers were blinded regarding the treatment for each subject. A total of 156 subjects were randomized; 144 had baseline and end-of-study biopsies, and 136 subjects completed the study. The ANA unexpectedly increased for all groups, with higher values correlating with clinical cutaneous inflammation. Nearly all of the adverse events were local cutaneous effects. One subject had cutaneous toxicity that required treatment discontinuation. Significantly more adverse events were seen in the groups taking diclofenac. Overall, the study indicated that the addition of topical DFMO to topical diclofenac did not enhance its activity. Both agents caused inflammation on a cellular and clinical level, which may have confounded the measurement of chemopreventative effects. More significant effects may be observed in subjects with greater baseline cutaneous damage.

show abstract

Levels of Rectal Mucosal Polyamines and Prostaglandin E2 Predict Ability of DFMO and Sulindac to Prevent Colorectal Adenoma

Cited by 49 publications

References 17 publications

Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids

Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids

Evaluation of Difluoromethylornithine for the Chemoprevention of Barrett's Esophagus and Mucosal Dysplasia

Phase IIB Randomized Study of Topical Difluoromethylornithine and Topical Diclofenac on Sun-Damaged Skin of the Forearm

Contact Info

Product

Resources

About