ENPP2 inhibitor improves proliferation in AOM/DSS-induced colorectal cancer mice via remodeling the gut barrier function and gut microbiota composition

Yan, Junling; Duan, Wenting; Gao, Qinhan; Mao, Tianxiao; Wang, Majie; Duan, Jialin; Li, Jiankang

doi:10.1016/j.phrs.2023.106877

Cited by 2 publications

(3 citation statements)

References 44 publications

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“…However, NOTUM becomes a specific oncogene when it develops into adenocarcinoma with p53 deletion ( Tian et al., 2023 ). Oncogenic microbial communities wield the ability to reshape the entire gut microbiota’s composition, inciting pro-inflammatory reactions and incipient cellular metamorphosis, culminating in carcinogenesis ( Yan et al., 2023 ). Furthermore, oncogenic microbiota catalyze CRC progression through the instigation of DNA damage within the epithelial cells.…”

Section: The Occurrence and Development Of Crcmentioning

confidence: 99%

Gut microbiome: decision-makers in the microenvironment of colorectal cancer

Han,

Zhang,

Zhang

et al. 2023

Front. Cell. Infect. Microbiol.

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Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract, accounting for the second most common cause of gastrointestinal tumors. As one of the intestinal barriers, gut bacteria form biofilm, participate in intestinal work, and form the living environment of intestinal cells. Metagenomic next-generation sequencing (mNGS) of the gut bacteria in a large number of CRC patients has been established, enabling specific microbial signatures to be associated with colorectal adenomato-carcinoma. Gut bacteria are involved in both benign precursor lesions (polyps), in situ growth and metastasis of CRC. Therefore, the term tumorigenic bacteria was proposed in 2018, such as Escherichia coli, Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, etc. Meanwhile, bacteria toxins (such as cytolethal distending toxin (CDT), Colibactin (Clb), B. fragilis toxin) affect the tumor microenvironment and promote cancer occurrence and tumor immune escape. It is important to note that there are differences in the bacteria of different types of CRC. In this paper, the role of tumorigenic bacteria in the polyp-cancer transformation and the effects of their secreted toxins on the tumor microenvironment will be discussed, thereby further exploring new ideas for the prevention and treatment of CRC.

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Section: The Occurrence and Development Of Crcmentioning

confidence: 99%

Gut microbiome: decision-makers in the microenvironment of colorectal cancer

Han,

Zhang,

Zhang

et al. 2023

Front. Cell. Infect. Microbiol.

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Section: Introductionmentioning

confidence: 99%

“…Nevertheless, the clinical management of CRC is riddled with challenges, most prominently due to inherent drug resistance mechanisms and a myriad of other molecular complexities. 14 In this therapeutic quest, nature's vast arsenal of molecules has often been the starting point for the identification of efficacious drug candidates, mainly attributed to their innate pharmacological properties and favourable safety profiles. 15 In this vast natural repository, 2,4‐ditert‐butylphenol (2,4‐DTBP), a lipophilic phytocompound, 16 , 17 , 18 , 19 stands out with its plethora of biological activities that span from antioxidant, 20 , 21 anti‐inflammatory 22 and antimicrobial 23 , 24 , 25 , 26 , 27 to notable anti‐cancer properties.…”

Section: Introductionmentioning

confidence: 99%

Targeted inhibition of colorectal cancer proliferation: The dual‐modulatory role of 2,4‐DTBP on anti‐apoptotic Bcl‐2 and Survivin proteins

Saha,

Hegde,

Chakraborty

et al. 2024

J Cellular Molecular Medi

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The anti‐apoptotic proteins, Bcl‐2 and Survivin, are consistently overexpressed in numerous human malignancies, notably in colorectal cancer. 2,4‐Di‐tert‐butylphenol (2,4‐DTBP) is a naturally occurring phenolic compound known for its diverse biological activities, including anti‐cancer properties. The mechanism behind 2,4‐DTBP‐induced inhibition of cell proliferation and apoptosis in human colorectal cancer cells, specifically regarding Bcl‐2 and Survivin, remains to be elucidated. In this study, we employed both in silico and in vitro methodologies to underpin this interaction at the molecular level. Molecular docking demonstrated a substantial binding affinity of 2,4‐DTBP towards Bcl‐2 (ΔG = −9.8 kcal/mol) and Survivin (ΔG = −5.6 kcal/mol), suggesting a potential inhibitory effect. Further, molecular dynamic simulations complemented by MM‐GBSA calculations confirmed the significant binding of 2,4‐DTBP with Bcl‐2 (dGbind = −54.85 ± 6.79 kcal/mol) and Survivin (dGbind = −32.36 ± 1.29 kcal/mol). In vitro assays using HCT116 colorectal cancer cells revealed that 2,4‐DTBP inhibited proliferation and promoted apoptosis in both a dose‐ and time‐dependent manner. Fluorescence imaging and scanning electron microscopy illustrated the classical features associated with apoptosis upon 2,4‐DTBP exposure. Cell cycle analysis through flow cytometry highlighted a G1 phase arrest and apoptosis assay demonstrated increased apoptotic cell population. Notably, western blotting results indicated a decreased expression of Bcl‐2 and Survivin post‐treatment. Considering the cytoprotective roles of Bcl‐2 and Survivin through the inhibition of mitochondrial dysfunction, our findings of disrupted mitochondrial bioenergetics, characterized by reduced ATP production and oxygen consumption, further accentuate the functional impairment of these proteins. Overall, the integration of in silico and in vitro data suggests that 2,4‐DTBP holds promise as a therapeutic agent targeting Bcl‐2 and Survivin in colorectal cancer.

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ENPP2 inhibitor improves proliferation in AOM/DSS-induced colorectal cancer mice via remodeling the gut barrier function and gut microbiota composition

Cited by 2 publications

References 44 publications

Gut microbiome: decision-makers in the microenvironment of colorectal cancer

Gut microbiome: decision-makers in the microenvironment of colorectal cancer

Targeted inhibition of colorectal cancer proliferation: The dual‐modulatory role of 2,4‐DTBP on anti‐apoptotic Bcl‐2 and Survivin proteins

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