An ultralow dose of the NADPH oxidase inhibitor diphenyleneiodonium (DPI) is an economical and effective therapeutic agent for the treatment of colitis-associated colorectal cancer

Kuai, Yue; Líu, Hao; Liu, Dongyu; Liu, Yunlong; Sun, Yongbing; Xie, Jiaxin; Sun, Jiachun; Yao, Fang; Pan, Hongming; Han, Weidong

doi:10.7150/thno.43938

Cited by 21 publications

(12 citation statements)

References 59 publications

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“…In other words. The activation of NF-κB and MAPK is mainly because TLR is stimulated and activated by harmful bacteria ( Xie et al., 2015 ; Kuai et al., 2020 ). In our study, AB23A intervention reversed the microbiota disorder and shifted it toward levels similar to those in the control group, which reduced stimulation of pathogenic microorganism on TLR (TLR4, TLR5).…”

Section: Discussionmentioning

confidence: 99%

Alisol B 23-Acetate Ameliorates Azoxymethane/Dextran Sodium Sulfate-Induced Male Murine Colitis-Associated Colorectal Cancer via Modulating the Composition of Gut Microbiota and Improving Intestinal Barrier

Zhu

Jia

Fan

et al. 2021

Front. Cell. Infect. Microbiol.

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Hunting for natural compounds that can modulate the structure of the intestinal flora is a new hotspot for colitis‐associated cancer (CAC) prevention or treatment. Alisol B 23-acetate (AB23A) is a natural tetracyclic triterpenoid found in Alismatis rhizoma which is well known for dietary herb. Alismatis rhizoma is often used clinically to treat gastrointestinal diseases in China. In this study, we investigated the potential prevention of AB23A in male mouse models of azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CAC. AB23A intervention alleviated the body weight loss, disease activity index, colon tumor load, tissue injury, and inflammatory cytokine changes in CAC mice. AB23A intervention leads to remarkable reductions in the activation of TLR, NF-κB and MAPK. AB23A significantly decreased the phosphorylation of p38, ERK, and JNK and up-regulated mucin-2 and the expression of tight junction proteins. The gut microbiota of AB23A-interfered mice was characterized with high microbial diversity, the reduced expansion of pathogenic bacteria, such as Klebsiella, Citrobacter, and Akkermansia, and the increased growth of bacteria including Bacteroides, Lactobacillus, and Alloprevotella. These data reveal that AB23A has the potential to be used to treat CAC in the future.

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Section: Discussionmentioning

confidence: 99%

Alisol B 23-Acetate Ameliorates Azoxymethane/Dextran Sodium Sulfate-Induced Male Murine Colitis-Associated Colorectal Cancer via Modulating the Composition of Gut Microbiota and Improving Intestinal Barrier

Zhu

Jia

Fan

et al. 2021

Front. Cell. Infect. Microbiol.

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“…These results clearly indicate that preventive administration of SJW can decrease both the occurrence of colorectal tumors and the associated induction of inflammatory signaling [ 150 ]. Interestingly, the same mouse model of colorectal carcinogenesis has recently been showed to depend on NOX/ROS activity, since a low dose of diphenyleneiodonium (DPI), a NOX inhibitor, prevents the formation of azoxymethane-induced adenomatous polyps and inhibits the intestinal inflammatory response [ 151 ]. Mechanistically, DPI decreases ROS production in the colon, resulting in inhibition of TNF-α, IL-6 and monocyte chemoattractant protein-1 (MCP-1) production, as well as ERK1/2, STAT-3 and NF-κB signaling, finally exerting a strong anti-inflammatory effect [ 151 ].…”

Section: Antitumor Activity Of Sjw Extract and Its Component Hpfmentioning

confidence: 99%

“…Interestingly, the same mouse model of colorectal carcinogenesis has recently been showed to depend on NOX/ROS activity, since a low dose of diphenyleneiodonium (DPI), a NOX inhibitor, prevents the formation of azoxymethane-induced adenomatous polyps and inhibits the intestinal inflammatory response [ 151 ]. Mechanistically, DPI decreases ROS production in the colon, resulting in inhibition of TNF-α, IL-6 and monocyte chemoattractant protein-1 (MCP-1) production, as well as ERK1/2, STAT-3 and NF-κB signaling, finally exerting a strong anti-inflammatory effect [ 151 ]. Thus, it is likely that DPI and SJW exert protective effects against azoxymethane-elicited colorectal carcinogenesis with a similar mechanism, i.e., by interfering with ROS-mediated inflammatory signaling.…”

Section: Antitumor Activity Of Sjw Extract and Its Component Hpfmentioning

confidence: 99%

Anti-Tumor Activity of Hypericum perforatum L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics

2020

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In this paper we review the mechanisms of the antitumor effects of Hypericum perforatum L. (St. John’s wort, SJW) and its main active component hyperforin (HPF). SJW extract is commonly employed as antidepressant due to its ability to inhibit monoamine neurotransmitters re-uptake. Moreover, further biological properties make this vegetal extract very suitable for both prevention and treatment of several diseases, including cancer. Regular use of SJW reduces colorectal cancer risk in humans and prevents genotoxic effects of carcinogens in animal models. In established cancer, SJW and HPF can still exert therapeutic effects by their ability to downregulate inflammatory mediators and inhibit pro-survival kinases, angiogenic factors and extracellular matrix proteases, thereby counteracting tumor growth and spread. Remarkably, the mechanisms of action of SJW and HPF include their ability to decrease ROS production and restore pH imbalance in tumor cells. The SJW component HPF, due to its high lipophilicity and mild acidity, accumulates in membranes and acts as a protonophore that hinders inner mitochondrial membrane hyperpolarization, inhibiting mitochondrial ROS generation and consequently tumor cell proliferation. At the plasma membrane level, HPF prevents cytosol alkalization and extracellular acidification by allowing protons to re-enter the cells. These effects can revert or at least attenuate cancer cell phenotype, contributing to hamper proliferation, neo-angiogenesis and metastatic dissemination. Furthermore, several studies report that in tumor cells SJW and HPF, mainly at high concentrations, induce the mitochondrial apoptosis pathway, likely by collapsing the mitochondrial membrane potential. Based on these mechanisms, we highlight the SJW/HPF remarkable potentiality in cancer prevention and treatment.

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“…The long-term inflammatory response can provide an ideal microenvironment for the development and growth of tumor cells, so it is believed to promote carcinogenesis. 20 As an important component of the chemokine family, CXC chemokines have been revealed to directly affect tumor transformation, survival, growth, invasion, and metastasis, and indirectly affect tumor development by affecting angiogenesis and crosstalk between tumor cells and interstitial cells. 21 Crosstalk between cancer cells and immune cells is a key part of tumorigenesis, metastasis, and therapeutic effects for patients with malignancies.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance and Therapeutic Target of CXC Chemokines in the Microenvironment of Lung Adenocarcinoma

Wang¹,

Li²,

Qi³

et al. 2022

IJGM

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Background: Lung adenocarcinoma (LUAD) is one of the most important subtypes of lung cancer and has a high morbidity and mortality. Inflammatory CXC chemokines in tumor microenvironment can stimulate tumor growth, invasion, and metastasis, affecting the prognosis of patients. However, the differential expression profiles, prognostic values, and specific mechanisms of the CXC chemokine family in LUAD have not been clarified. Methods: Transcriptome expression profile data were extracted from TIMER and TCGA. GEPIA was used to compare the relationship between CXC chemokines and clinicopathologic parameters. The prognostic analysis was performed using a Kaplan-Meier curve in GEPIA. LinkedOmics and TRRUST were applied to conduct the enrichment analysis of the regulatory networks containing the kinase targets, miRNA targets, and transcriptional factor targets. The characteristics of immune infiltration and immune-related clinical outcomes were evaluated with TIMER algorithms. Single-cell RNA sequencing localization analysis of genes as prognostic biomarkers were performed by PanglaoDB. Results: Nine differentially expressed genes were identified in LUAD compared to normal tissues. Aberrant expression of CXCL2 (P =0.0017), CXCL13 (P= 0.0271), CXCL16 (P= 0.016), and CXCL17 (P= 2.14e-5) was significantly correlated with clinical cancer stage. Furthermore, patients with low gene transcription of CXCL 7 (P = 0.017) and high expression of CXCL 17 (P = 0.00045) had a better prognosis in LUAD. We also found that immune cell infiltration was significantly correlated with LUAD microenvironment mediated by CXC chemokines. Cox proportional hazard model test was conducted and indicated that B cell infiltration could prolong the survival of the LUAD patients. CXCL17 exerted anti-tumors effect through pulmonary alveolar type II cells according to singlecell analysis. Conclusion: Our research identified the aberrant expression profiles and prognostic biomarkers of CXC chemokines in LUAD. This detailed analysis of the regulatory factor networks for CXC chemokine gene expression may provide novel insights for selecting potential immunotherapeutic targets.

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An ultralow dose of the NADPH oxidase inhibitor diphenyleneiodonium (DPI) is an economical and effective therapeutic agent for the treatment of colitis-associated colorectal cancer

Cited by 21 publications

References 59 publications

Alisol B 23-Acetate Ameliorates Azoxymethane/Dextran Sodium Sulfate-Induced Male Murine Colitis-Associated Colorectal Cancer via Modulating the Composition of Gut Microbiota and Improving Intestinal Barrier

Alisol B 23-Acetate Ameliorates Azoxymethane/Dextran Sodium Sulfate-Induced Male Murine Colitis-Associated Colorectal Cancer via Modulating the Composition of Gut Microbiota and Improving Intestinal Barrier

Anti-Tumor Activity of Hypericum perforatum L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics

Prognostic Significance and Therapeutic Target of CXC Chemokines in the Microenvironment of Lung Adenocarcinoma

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