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Fulltext Roles of phosphatidylinositol-3-kinases signaling pathway in inflammation-related cancer: Impact of rs10889677 variant and buparlisib in colitis-associated cancer

Razali NN, Raja Ali RA, Muhammad Nawawi KN, Yahaya A, Mohd Rathi ND, Mokhtar NM

World J Gastroenterol, 2023 Oct 28;29(40):5543-5556.
PMID: 37970476 DOI: 10.3748/wjg.v29.i40.5543

BACKGROUND: Phosphatidylinositol-3-kinases (PI3K) is a well-known route in inflammation-related cancer. Recent discovery on PI3K-related genes revealed a potential variant that links ulcerative colitis (UC) and colorectal cancer (CRC) with colitis-associated cancer (CAC). PI3K/AKT pathway has been recommended as a potential additional therapeutic option for CRC due to its substantial role in modifying cellular processes. Buparlisib is a pan-class I PI3K inhibitor previously shown to reduce tumor growth.
AIM: To investigate the regulation of rs10889677 and the role of buparlisib in the PI3K signaling pathway in CAC pathogenesis.
METHODS: Genomic DNA from 32 colonic samples, including CAC (n = 7), UC (n = 10) and CRC (n = 15), was sequenced for the rs10889677 mutation. The mutant and wildtype fragments were amplified and cloned in the pmirGLO vector. The luciferase activity of cloned vectors was assessed after transfection into the HT29 cell line. CAC mice were induced by a mixture of a single azoxymethane injection and three cycles of dextran sulphate sodium, then buparlisib was administered after 14 d. The excised colon was subjected to immunohistochemistry for Ki67 and Cleaved-caspase-3 markers and quantitative real-time polymerase chain reaction analysis for Pdk1 and Sgk2.
RESULTS: Luciferase activity decreased by 2.07-fold in the rs10889677 mutant, confirming the hypothesis that the variant disrupted miRNA binding sites, which led to an increase in IL23R expression and the activation of the PI3K signaling pathway. Furthermore, CAC-induced mice had a significantly higher disease activity index (P < 0.05). Buparlisib treatment significantly decreased mean weight loss in CAC-induced mice (P < 0.05), reduced the percentage of proliferating cells by 5%, and increased the number of apoptotic cells. The treatment also caused a downward trend of Pdk1 expression and significantly decreased Sgk2 expression.
CONCLUSION: Our findings suggested that the rs10889677 variant as a critical initiator of the PI3K signaling pathway, and buparlisib had the ability to prevent PI3K-non-AKT activation in the pathophysiology of CAC.

Matched MeSH terms: Colitis/chemically induced
Treatment with bindarit, an inhibitor of MCP-1 synthesis, protects mice against trinitrobenzene sulfonic acid-induced colitis

Bhatia M, Landolfi C, Basta F, Bovi G, Ramnath RD, de Joannon AC, et al.

Inflamm Res, 2008 Oct;57(10):464-71.
PMID: 18827968 DOI: 10.1007/s00011-008-7210-y

Chemokines play a fundamental role in trafficking and activation of leukocytes in colonic inflammation. We investigated the ability of bindarit, an inhibitor of monocyte chemoattractant protein-1 (MCP-1/CCL2) synthesis, to inhibit chemokine production by human intestinal epithelial cells (HT-29) and its effect in trinitro-benzene sulfonic acid (TNBS)-induced colitis in mice.

Matched MeSH terms: Colitis/chemically induced*
Native κ-carrageenan induced-colitis is related to host intestinal microecology

Mi Y, Chin YX, Cao WX, Chang YG, Lim PE, Xue CH, et al.

Int J Biol Macromol, 2020 Mar 15;147:284-294.
PMID: 31926226 DOI: 10.1016/j.ijbiomac.2020.01.072

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, has gradually emerged as a public health challenge worldwide. Carrageenan is a popular food additive that has been in use for decades. However, controversy exists regarding to the safety of carrageenan due to its exacerbation of colitis in experimental models. In this study, we studied the effects of vehicle and host intestinal microflora on carrageenan inflammatory properties in C57BL/6 J mice. We found that in high-fat diet model, native carrageenan in drinking water increased the disease activity index (DAI), myeloperoxidase (MPO) activity and the mRNA expression of TLR4 in colon, whereas carrageenan-supplemented diet has no visible effects. However, no signs of colitis were observed under low-fat diet regardless of the mode of vehicle used. Moreover, we discovered that carrageenan-induced colitis in high-fat diet model was robustly correlated with changes in the composition of gut microbiota, specifically Alistipes finegoldii and Bacteroides acidifaciens. Hence, we propose that the inflammatory property of carrageenan is influenced greatly by its intake form via modification of host intestinal microecology.

Matched MeSH terms: Colitis/chemically induced*
Boldine suppresses dextran sulfate sodium-induced mouse experimental colitis: NF-κB and IL-6/STAT3 as potential targets

Pandurangan AK, Mohebali N, Hasanpourghadi M, Looi CY, Mustafa MR, Mohd Esa N

Biofactors, 2016 May;42(3):247-58.
PMID: 26891685 DOI: 10.1002/biof.1267

Ulcerative colitis (UC) is a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration, and upregulation of inflammatory mediators. Boldine is an alkaloid compound found in Boldo tree, with multiple pharmacological actions, mainly anti-inflammatory, antioxidant, antitumor, and immunomodulatory activities. Hence, the effect of boldine for its anti-inflammatory properties against dextran sulfate sodium (DSS)-induced UC in BALB/c mice was studied. Administration of boldine to DSS-induced mice protects colon damage by reduced disease activity index, spleen weight, and increased colon length. Also administration of boldine showed a reduction in the activity of myeloperoxidase (MPO) and CD 68+ expression. Boldine reduced the colon damage, with significant reductions in both the extent and the severity of the inflammation as well as in crypt damage and leukocyte infiltration in the mucosa. Analysis in vivo showed clear decrease in the production of tumor necrosis factor (TNF)-α, Interleukin (IL)-6, IL-17, and signal transducer and activator of transcription-(p-STAT3)(Y705) with nuclear factor (p65-NF-κB) production being reduced significantly. Moreover, p65-NF-κB activation was reduced in mouse macrophage RAW 264.7 cells in vitro. The data demonstrated that boldine may be beneficial in colitis through selective immunomodulatory effects, which may be mediated, at least in part, by inhibition of p65-NF-κB and STAT3 signaling pathways. © 2016 BioFactors, 42(3):247-258, 2016.

Matched MeSH terms: Colitis/chemically induced
Fulltext Gallic acid attenuates dextran sulfate sodium-induced experimental colitis in BALB/c mice

Pandurangan AK, Mohebali N, Norhaizan ME, Looi CY

Drug Des Devel Ther, 2015;9:3923-34.
PMID: 26251571 DOI: 10.2147/DDDT.S86345

Gallic acid (GA) is a polyhydroxy phenolic compound that has been detected in various natural products, such as green tea, strawberries, grapes, bananas, and many other fruits. In inflammatory bowel disease, inflammation is promoted by oxidative stress. GA is a strong antioxidant; thus, we evaluated the cytoprotective and anti-inflammatory role of GA in a dextran sulfate sodium (DSS)-induced mouse colitis model. Experimental acute colitis was induced in male BALB/c mice by administering 2.5% DSS in the drinking water for 7 days. The disease activity index; colon weight/length ratio; histopathological analysis; mRNA expressions of IL-21 and IL-23; and protein expression of nuclear erythroid 2-related factor 2 (Nrf2) were compared between the control and experimental mice. The colonic content of malondialdehyde and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity were examined as parameters of the redox state. We determined that GA significantly attenuated the disease activity index and colon shortening, and reduced the histopathological evidence of injury. GA also significantly (P<0.05) reduced the expressions of IL-21 and IL-23. Furthermore, GA activates/upregulates the expression of Nrf2 and its downstream targets, including UDP-GT and NQO1, in DSS-induced mice. The findings of this study demonstrate the protective effect of GA on experimental colitis, which is probably due to an antioxidant nature of GA.

Matched MeSH terms: Colitis/chemically induced
Fulltext Genome-wide CRISPR screen identifies LGALS2 as an oxidative stress-responsive gene with an inhibitory function on colon tumor growth

Li H, Zhao L, Lau YS, Zhang C, Han R

Oncogene, 2021 01;40(1):177-188.
PMID: 33110234 DOI: 10.1038/s41388-020-01523-5

Colorectal cancer is the third leading cause of cancer-related deaths in the United States and the third most common cancer in men and women. Around 20% colon cancer cases are closely linked with colitis. Both environmental and genetic factors are thought to contribute to colon inflammation and tumor development. However, the genetic factors regulating colitis and colon tumorigenesis remain elusive. Since reactive oxygen species (ROS) is vitally involved in tissue inflammation and tumorigenesis, here we employed a genome-wide CRISPR knockout screening approach to systemically identify the genetic factors involved in the regulation of oxidative stress. Next generation sequencing (NGS) showed that over 600 gRNAs including the ones targeting LGALS2 were highly enriched in cells survived after sublethal H2O2 challenge. LGALS2 encodes the glycan-binding protein Galectin 2 (Gal2), which is predominantly expressed in the gastrointestinal tract and downregulated in human colon tumors. To examine the role of Gal2 in colitis, we employed the dextran sodium sulfate (DSS)-induced acute colitis model in mice with (WT) or without Lgals2 (Gal2-KO) and showed that Gal2 deficiency ameliorated DSS-induced colitis. We further demonstrated that Gal2-KO mice developed significantly larger tumors than WT mice using Azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal cancer model. We found that STAT3 phosphorylation was significantly increased in Gal2-deficient tumors as compared to those in WT mice. Gal2 overexpression decreased the proliferation of human colon tumor epithelial cells and blunted H2O2-induced STAT3 phosphorylation. Overall, our results demonstrate that Gal2 plays a suppressive role in colon tumor growth and highlights the therapeutic potential of Gal2 in colon cancer.

Matched MeSH terms: Colitis/chemically induced
Fulltext Fucoidan Extracts Ameliorate Acute Colitis

Lean QY, Eri RD, Fitton JH, Patel RP, Gueven N

PLoS One, 2015;10(6):e0128453.
PMID: 26083103 DOI: 10.1371/journal.pone.0128453

Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are an important cause of morbidity and impact significantly on quality of life. Overall, current treatments do not sustain a long-term clinical remission and are associated with adverse effects, which highlight the need for new treatment options. Fucoidans are complex sulphated, fucose-rich polysaccharides, found in edible brown algae and are described as having multiple bioactivities including potent anti-inflammatory effects. Therefore, the therapeutic potential of two different fucoidan preparations, fucoidan-polyphenol complex (Maritech Synergy) and depyrogenated fucoidan (DPF) was evaluated in the dextran sulphate sodium (DSS) mouse model of acute colitis. Mice were treated once daily over 7 days with fucoidans via oral (Synergy or DPF) or intraperitoneal administration (DPF). Signs and severity of colitis were monitored daily before colons and spleens were collected for macroscopic evaluation, cytokine measurements and histology. Orally administered Synergy and DPF, but not intraperitoneal DPF treatment, significantly ameliorated symptoms of colitis based on retention of body weight, as well as reduced diarrhoea and faecal blood loss, compared to the untreated colitis group. Colon and spleen weight in mice treated with oral fucoidan was also significantly lower, indicating reduced inflammation and oedema. Histological examination of untreated colitis mice confirmed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and oedema, while all aspects of this pathology were alleviated by oral fucoidan. Importantly, in this model, the macroscopic changes induced by oral fucoidan correlated significantly with substantially decreased production of at least 15 pro-inflammatory cytokines by the colon tissue. Overall, oral fucoidan preparations significantly reduce the inflammatory pathology associated with DSS-induced colitis and could therefore represent a novel nutraceutical option for the management of IBD.

Matched MeSH terms: Colitis/chemically induced
Fulltext Orally Administered Enoxaparin Ameliorates Acute Colitis by Reducing Macrophage-Associated Inflammatory Responses

Lean QY, Eri RD, Randall-Demllo S, Sohal SS, Stewart N, Peterson GM, et al.

PLoS One, 2015;10(7):e0134259.
PMID: 26218284 DOI: 10.1371/journal.pone.0134259

Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life. The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects. This prompts the need for new treatment modalities. Enoxaparin, a widely used antithrombotic agent, is reported to possess anti-inflammatory properties and therefore we evaluated its therapeutic potential in a mouse model of colitis. Acute colitis was induced in male C57BL/6 mice by administration of dextran sulfate sodium (DSS). Mice were treated once daily with enoxaparin via oral or intraperitoneal administration and monitored for colitis activities. On termination (day 8), colons were collected for macroscopic evaluation and cytokine measurement, and processed for histology and immunohistochemistry. Oral but not intraperitoneal administration of enoxaparin significantly ameliorated DSS-induced colitis. Oral enoxaparin-treated mice retained their body weight and displayed less diarrhea and fecal blood loss compared to the untreated colitis group. Colon weight in enoxaparin-treated mice was significantly lower, indicating reduced inflammation and edema. Histological examination of untreated colitis mice showed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and the presence of edema, while all aspects of this pathology were alleviated by oral enoxaparin. Reduced number of macrophages in the colon of oral enoxaparin-treated mice was accompanied by decreased levels of pro-inflammatory cytokines. Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis.

Matched MeSH terms: Colitis/chemically induced
Dietary cocoa protects against colitis-associated cancer by activating the Nrf2/Keap1 pathway

Pandurangan AK, Saadatdoust Z, Esa NM, Hamzah H, Ismail A

Biofactors, 2015 Jan-Feb;41(1):1-14.
PMID: 25545372 DOI: 10.1002/biof.1195

Colorectal cancer (CRC) is the third most common malignancy in males and the second most common cancer worldwide. Chronic colonic inflammation is a known risk factor for CRC. Cocoa contains many polyphenolic compounds that have beneficial effects in humans. The objective of this study is to explore the antioxidant properties of cocoa in the mouse model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated cancer, focusing on the activation of Nrf2 signaling. Mice were treated with AOM/DSS and randomized to receive either a control diet or a 5 and 10% cocoa diet during the study period. On day 62 of the experiment, the entire colon was processed for biochemical and histopathological examination and further evaluations. Increased levels of malondialdehyde (MDA) were observed in AOM/DSS-induced mice; however, subsequent administration of cocoa decreased the MDA. Enzymatic and nonenzymatic antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, were decreased in the AOM/DSS mice. Cocoa treatment increases the activities/levels of enzymatic and nonenzymatic antioxidants. Inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, were elevated during AOM/DSS-induction, and treatment with 5 and 10% cocoa effectively decreases the expression of iNOS and COX-2. The NF-E2-related factor 2 and its downstream targets, such as NQO1 and UDP-GT, were increased by cocoa treatment. The results of our study suggest that cocoa may merit further clinical investigation as a chemopreventive agent that helps prevent CAC.

Matched MeSH terms: Colitis/chemically induced