Entropy-driven binding of gut bacterial β-glucuronidase inhibitors ameliorates irinotecan-induced toxicity

Lin, Hong-Shiang; Chen, Chia-Yu; Lin, Ting-Chien; Yeh, Lun-Fu; Hsieh, Wei-Che; Gao, Shijay; Burnouf, Pierre-Alain; Chen, Bing‐Mae; Hsieh, T.J.; Dashnyam, P.; Kuo, Yen-Hsi; Tu, Zhijay; Roffler, Steve R.; Lin, Chun‐Hung

doi:10.1038/s42003-021-01815-w

Cited by 25 publications

(17 citation statements)

References 35 publications

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“…26 For example, pyrazolo [4,3-c]quinoline derivatives (TCH-3562) and uronic isofagomine derivatives could reduce CPT-11-induced complications without impairing its efficacy. [27][28][29] Reducing CPT-11 toxicity could in turn increase patients' tolerance to higher dosage, leading to better therapeutic outcomes. 30 This example illustrates the reciprocal interactions between commensal bacteria and chemotherapy, demonstrating the potential of microbiota modulation in reducing therapeutic toxicity and enhancing efficacy.…”

Section: Gut Bacteria and Pharmacokinetics Of Chemotherapymentioning

confidence: 99%

“…Selective β-glucuronidase inhibitors have now been developed to prevent CPT-11-induced microbial alteration and epithelial damage 26. For example, pyrazolo[4,3-c]quinoline derivatives (TCH-3562) and uronic isofagomine derivatives could reduce CPT-11-induced complications without impairing its efficacy 27–29. Reducing CPT-11 toxicity could in turn increase patients’ tolerance to higher dosage, leading to better therapeutic outcomes 30.…”

Section: Microbiota and Chemotherapymentioning

confidence: 99%

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Cancer pharmacomicrobiomics: targeting microbiota to optimise cancer therapy outcomes

Ting

Lau

2022

Gut

127

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Despite the promising advances in novel cancer therapy such as immune checkpoint inhibitors (ICIs), limitations including therapeutic resistance and toxicity remain. In recent years, the relationship between gut microbiota and cancer has been extensively studied. Accumulating evidence reveals the role of microbiota in defining cancer therapeutic efficacy and toxicity. Unlike host genetics, microbiota can be easily modified via multiple strategies, including faecal microbiota transplantation (FMT), probiotics and antibiotics. Preclinical studies have identified the mechanisms on how microbes influence cancer treatment outcomes. Clinical trials have also demonstrated the potential of microbiota modulation in cancer treatments. Herein, we review the mechanistic insights of gut microbial interactions with chemotherapy and ICIs, particularly focusing on the interplay between gut bacteria and the pharmacokinetics (eg, metabolism, enzymatic degradation) or pharmacodynamics (eg, immunomodulation) of cancer treatment. The translational potential of basic findings in clinical settings is then explored, including using microbes as predictive biomarkers and microbial modulation by antibiotics, probiotics, prebiotics, dietary modulations and FMT. We further discuss the current limitations of gut microbiota modulation in patients with cancer and suggest essential directions for future study. In the era of personalised medicine, it is crucial to understand the microbiota and its interactions with cancer. Manipulating the gut microbiota to augment cancer therapeutic responses can provide new insights into cancer treatment.

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Section: Gut Bacteria and Pharmacokinetics Of Chemotherapymentioning

confidence: 99%

Section: Microbiota and Chemotherapymentioning

confidence: 99%

Cancer pharmacomicrobiomics: targeting microbiota to optimise cancer therapy outcomes

Ting

Lau

2022

Gut

127

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“…Intestinal GUSB hydrolyzes glucuronide metabolites into the toxic style of the intestine, causing intestinal damage. Selected inhibitors of GUSB presently under development may relieve diarrhea caused by irinotecan and can contribute to decreasing the incidence and altering the activity ( 24 , 25 ). However, there are not many studies on GUSB directly against cancer.…”

Section: Discussionmentioning

confidence: 99%

Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma

et al. 2022

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Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC.

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“…There has been significant interest over recent years in understanding how the inhibition of bacterial GUS can alleviate intestinal mucositis. Various inhibitors against E. coli GUS enzyme have been designed, which were shown to actively protect mice from CPT11-induced mucositis without causing cellular injury ( Roberts et al, 2013 ; Pollet et al, 2017 ; Lin et al, 2021 ). Therefore, we performed molecular docking assays using E. coli GUS protein and found that berberine could enter a pocket domain of GUS with low binding energy.…”

Section: Discussionmentioning

confidence: 99%

Berberine Improves Irinotecan-Induced Intestinal Mucositis Without Impairing the Anti-colorectal Cancer Efficacy of Irinotecan by Inhibiting Bacterial β-glucuronidase

Yue

Gao

et al. 2021

Front. Pharmacol.

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Irinotecan (CPT11), a broad-spectrum cytotoxic anticancer agent, induces a series of toxic side-effects. The most conspicuous side-effect is gastrointestinal mucositis, including nausea, vomiting, and diarrhea. A growing body of evidence indicates that bacteria β-glucuronidase (GUS), an enzyme expressed by intestinal microbiota, converts the inactive CPT11 metabolite SN38G to the active metabolite SN38 to ultimately induce intestinal mucositis. We sought to explore the potential efficacy and underlying mechanisms of berberine on CPT11-induced mucositis. Our study showed that berberine (50 mg/kg; i. g.) mitigated the CPT11-induced loss of mucosal architecture, ulceration, and neutrophil infiltration. Meanwhile, berberine improved mucosal barrier function by increasing the number of globlet cells, protecting trans-endothelial electrical resistance (TEER), reducing permeability and increasing tight junction proteins expression. LC-MS analysis showed that berberine decreased the content of SN38 in feces, which correlated with decreases in both GUS activity and GUS-producing bacteria. Further molecular docking and Lineweaver-Burk plots analyses suggested that berberine functions as a potential non-competitive inhibitor against GUS enzyme. Of note, berberine maintained the anti-tumor efficacy of CPT11 in a tumor xenograft model while abrogating the intestinal toxicity of CPT11. Overall, we identified for the first time the remission effects of berberine on intestinal mucositis induced by CPT11 without impairing the anti-colorectal cancer efficacy of CPT11 partially via inhibiting bacterial GUS enzyme.

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Entropy-driven binding of gut bacterial β-glucuronidase inhibitors ameliorates irinotecan-induced toxicity

Cited by 25 publications

References 35 publications

Cancer pharmacomicrobiomics: targeting microbiota to optimise cancer therapy outcomes

Cancer pharmacomicrobiomics: targeting microbiota to optimise cancer therapy outcomes

Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma

Berberine Improves Irinotecan-Induced Intestinal Mucositis Without Impairing the Anti-colorectal Cancer Efficacy of Irinotecan by Inhibiting Bacterial β-glucuronidase

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