Prevention of Colitis-Associated Colorectal Cancer with 8-Hydroxydeoxyguanosine

Ock, Chan Young; Kim, Eun‐Hee; Hong, Hua; Hong, Kyung Sook; Han, Young‐Min; Choi, Ki-Seok; Hahm, Ki Baik; Chung, Myung‐Hee

doi:10.1158/1940-6207.capr-11-0161

Cited by 22 publications

(18 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2). In the previous studies we did not observe any histological changes in lung, liver, and intestines of mice with even much higher doses than 30 mg/kg [21,48,49]. Although 30 mg/kg is a fairly large dose in clinical terms, the dose of numerous pharmaceutical modifiers such as statins and fibrates tested in mouse models of atherosclerosis so far has ranged generally between 10 and 100 mg/kg/day [50].…”

Section: Discussionmentioning

confidence: 91%

8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation

Huh

Son

Lee

et al. 2012

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

8-Hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative stress, has been recently rediscovered to inhibit Rac1 in neutrophils and macrophages, thereby inhibiting Rac1-linked functions of these cells, including reactive oxygen species production through NADPH oxidase activation, phagocytosis, chemotaxis, and cytokine release. In vascular smooth muscle cells (VSMCs), reactive oxygen species also induce abnormal proliferation and migration leading to progression of atherosclerosis. Based upon the involvement of reactive oxygen species in phagocytic cells and VSMCs during the atherosclerotic process, we hypothesized that 8-OHdG could have antiatherosclerotic action and tested this hypothesis in an experimentally induced atherosclerosis in mice. Partially ligated ApoE knockout mice, a more physiologically relevant model of low and oscillatory flow, developed an advanced lesion in 2 weeks, and orally administered 8-OHdG significantly reduced plaque formation along with reduced superoxide formation, monocyte/macrophage infiltration, and extracellular matrix (ECM) accumulation. The effects of 8-OHdG observed in primary VSMCs were consistent with the in vivo effects of 8-OHdG and were inhibitory to angiotensin II or platelet-derived growth factor-induced production of reactive oxygen species, proliferation, migration, and ECM production. Also, angiotensin II-induced Rac1 activity in VSMCs was significantly inhibited by 8-OHdG, and transfection of constitutively active Rac1 reversed the inhibitory effect of 8-OHdG on VSMC activation. Molecular docking study showed that 8-OHdG stabilizes Rac1–GEF complex, indicating the physical contact of 8-OHdG with Rac1. These findings highly suggest that the antiatherosclerotic effect of 8-OHdG is mediated by inhibition of Rac1 activity. In conclusion, our results show a novel action of orally active 8-OHdG in suppressing atherosclerotic plaque formation in vivo and VSMC activation in vitro through inhibition of Rac1, which emphasizes a new therapeutic avenue to benefit atherosclerosis.

show abstract

Section: Discussionmentioning

confidence: 91%

8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation

Huh

Son

Lee

et al. 2012

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…Guanine nucleotide exchange factors (GEFs) promote activation of the Rho GTPase Rac1, which in the colon mediates the production of reactive oxygen species and activation of NF-κB, leading to stimulation of WNT signaling and expansion of the intestinal stem cell pool 91 . Interestingly, abrogation of Rac1 activity pharmacologically 92 or genetically 91 in animal models prevents the development of colon cancer, suggesting a potential therapeutic benefit from targeting the Rho and Rac pathway in IBD.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease−Associated Colorectal Cancers

et al. 2016

View full text Add to dashboard Cite

BACKGROUND & AIMS A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer (CRC). Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors. METHODS We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and CRC (15 with ulcerative colitis, 14 with Crohn’s disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the micro-dissected tumor and matched non-tumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies. RESULTS Two specimens had somatic mutations in the DNA-proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with and incidence prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for non-canonical WNT signaling in development of colorectal tumors in patients with IBD. CONCLUSIONS Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and CRC.

show abstract

“…However, until now, only a couple of drugs were commercially available to control IBD. In animal studies, antioxidants such as S-adenosylmethionine, green tea polyphenols, and 2(R,S)-n-propylthiazolidine-4(R)-carboxylic acid attenuated dextran sulfate sodium (DSS)-induced colitis, and exogenous 8-hydroxy-2′-deoxyguanosine paradoxically blocked Rac1 activation and subsequent nitrogen oxide (NO) inactivation in DSS-induced colitis and inflammation-associated carcinogenesis models[4-6]. In our previous studies, pantoprazole significantly reduced oxidative stress and the degree of colon inflammation through suppression of tumor necrosis factor-alpha (TNF-α) and NO in a DSS-induced colitis mouse model, and infliximab was suggested as a preventive drug in a colitis-associated carcinogenesis model[7,8].…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium-induced colitis model

Shin¹,

Cho²,

Kim³

et al. 2017

WJG

View full text Add to dashboard Cite

AIMTo evaluate the anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium (DSS)-induced colitis model.METHODSAn acute colitis mouse model was induced by oral administration of 5% DSS in the drinking water for 7 d. In the treated group, rosuvastatin (0.3 mg/kg per day) was administered orally before and after DSS administration for 21 d. On day 21, mice were sacrificed and the colons were removed for macroscopic examination, histology, and Western blot analysis. In the in vitro study, IEC-6 cells were stimulated with 50 ng/mL tumor necrosis factor (TNF)-α and then treated with or without rosuvastatin (2 μmol/L). The levels of reactive oxygen species (ROS), inflammatory mediators, and apoptotic markers were measured.RESULTSIn DSS-induced colitis mice, rosuvastatin treatment significantly reduced the disease activity index and histological damage score compared to untreated mice (P < 0.05). Rosuvastatin also attenuated the DSS-induced increase of 8-hydroxy-2’-deoxyguanosine and NADPH oxidase-1 expression in colon tissue. Multiplex ELISA analysis revealed that rosuvastatin treatment reduced the DSS-induced increase of serum IL-2, IL-4, IL-5, IL-6, IL-12 and IL-17, and G-CSF levels. The increased levels of cleaved caspase-3, caspase-7, and poly (ADP-ribose) polymerase in the DSS group were attenuated by rosuvastatin treatment. In vitro, rosuvastatin significantly reduced the production of ROS, inflammatory mediators and apoptotic markers in TNF-α-treated IEC-6 cells (P < 0.05).CONCLUSIONRosuvastatin had the antioxidant, anti-inflammatory and anti-apoptotic effects in DSS-induced colitis model. Therefore, it might be a candidate anti-inflammatory drug in patients with inflammatory bowel disease.

show abstract

Prevention of Colitis-Associated Colorectal Cancer with 8-Hydroxydeoxyguanosine

Cited by 22 publications

References 51 publications

8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation

8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation

Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease−Associated Colorectal Cancers

Anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium-induced colitis model

Contact Info

Product

Resources

About