Small-molecule inhibitors prevent the genotoxic and protumoural effects induced by colibactin-producing bacteria

Cougnoux, Antony; Delmas, Julien; Gibold, Lucie; Faïs, Tiphanie; Romagnoli, Chiara; Robin, Frédéric; Cuevas-Ramos, Gabriel; Oswald, Éric; Darfeuille‐Michaud, Arlette; Prati, Fabio; Dalmasso, Guillaume; Bonnet, Richard

doi:10.1136/gutjnl-2014-307241

Cited by 69 publications

(53 citation statements)

References 43 publications

(65 reference statements)

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“…In addition, cytolysis was investigated by measuring lactate dehydrogenase (LDH) release using an LDH kit (Roche Diagnostics) according to the manufacturer's recommendations [58]. …”

Section: Methodsmentioning

confidence: 99%

Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models

et al. 2016

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Hypoxia is a common feature of solid tumors that activates a plethora of pathways, resulting in proliferation and resistance of cancer cells to radio- and chemotherapy. Pheochromocytomas/paragangliomas (PHEOs/PGLs) with mutations in the gene coding for the subunit B of succinate dehydrogenase (SDHB) are the most aggressive forms of the disease, which is partially due to their pseudohypoxic character, metabolic abnormalities, and elevated reactive oxygen species (ROS) levels. We investigated the effect of piperlongumine (PL), a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular ROS levels, on PHEO cells. Here we report for the first time that PL mediates PHEO cell death by activating both apoptosis and necroptosis in vitro and in vivo. This effect is magnified in hypoxic conditions, making PL a promising potential candidate for use as a therapeutic option for patients with PHEO/PGL, including those with SDHB mutations.

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“…In addition, cytolysis was investigated by measuring lactate dehydrogenase (LDH) release using an LDH kit (Roche Diagnostics) according to the manufacturer's recommendations [58]. …”

Section: Methodsmentioning

confidence: 99%

Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models

et al. 2016

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“…Colonization of the gut by phylogroup B2 E. coli producing colibactin is associated with the presence of DNA double-strand breaks in intestinal epithelial cells (14). Phylogroup B2 E. coli bacteria producing colibactin have an impact on host physiology (14, 15) and contribute to the development of colorectal cancer in mouse models of colitis (16, 17). Infants are colonized at birth with B2 E. coli expressing colibactin, and these E. coli strains have a long-term capacity to persist in the bowel microbiota (14, 18).…”

Section: Introductionmentioning

confidence: 99%

The Food Contaminant Deoxynivalenol Exacerbates the Genotoxicity of Gut Microbiota

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Dobrindt

Martín

et al. 2017

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An increasing number of human beings from developed countries are colonized by Escherichia coli strains producing colibactin, a genotoxin suspected to be associated with the development of colorectal cancers. Deoxynivalenol (DON) is the most prevalent mycotoxin that contaminates staple food—especially cereal products—in Europe and North America. This study investigates the effect of the food contaminant DON on the genotoxicity of the E. coli strains producing colibactin. In vitro, intestinal epithelial cells were coexposed to DON and E. coli producing colibactin. In vivo, newborn rats colonized at birth with E. coli producing colibactin were fed a DON-contaminated diet. Intestinal DNA damage was estimated by the phosphorylation of histone H2AX. DON exacerbates the genotoxicity of the E. coli producing colibactin in a time- and dose-dependent manner in vitro. Although DON had no effect on the composition of the gut microbiota, and especially on the number of E. coli, a significant increase in DNA damage was observed in intestinal epithelial cells of animals colonized by E. coli strains producing colibactin and coexposed to DON compared to animals colonized with E. coli strains unable to produce colibactin or animals exposed only to DON. In conclusion, our data demonstrate that the genotoxicity of E. coli strains producing colibactin, increasingly present in the microbiota of asymptomatic human beings, is modulated by the presence of DON in the diet. This raises questions about the synergism between food contaminants and gut microbiota with regard to intestinal carcinogenesis.

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“…To date very few studies have proved that specifically targeting microbial protein might be useful in CCR. To our knowledge, only our study 29 and a study published by Wallace and colleagues have shown the feasibility of this approach. 30 Wallace and colleagues demonstrated in vivo that targeting bacterial b-glucoronidase abrogated the diarrhea induced by irinotecan (a secondary effect of chemotherapeutic drugs used in CRC).…”

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confidence: 60%

“…27,28 We therefore aimed at identifying small molecules able to bind and block the catalytic pocket of ClbP. 29 First, in silico docking experiments identified 2 boron-based compounds with computed ligand efficiency values consistent with results expected for medicinal chemistry leads. The crystalline structure of ClbP in complex with the compounds confirmed that they bound the active site of ClbP, in the immediate vicinity of the active serine.…”

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confidence: 99%

Targeting colorectal cancer-associated bacteria: A new area of research for personalized treatments

et al. 2016

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Most cases of colorectal cancer (CRC) are sporadic, and numerous studies have suggested that gut microbiota may play a crucial role in CRC development. Escherichia coli is a member of the gut microbiota frequently associated with colorectal tumors. CRC-associated E. coli strains frequently harbor the pks genomic island. This genomic island is responsible for the synthesis of colibactin genotoxin, which increases tumor numbers in CRC mouse models. We recently showed that targeting ClbP, a key enzyme involved in colibactin synthesis, blocks the deleterious effect of this toxin in vitro and leads to a significant decrease in tumor numbers in vivo. Altogether, our results suggest that the personalized treatment of CRC should also take into consideration the bacteria associated with the tumor in order to limit their deleterious effects.

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Small-molecule inhibitors prevent the genotoxic and protumoural effects induced by colibactin-producing bacteria

Abstract: These results demonstrate that targeting colibactin production controls the genotoxic and protumoural effects induced by this toxin.

Cited by 69 publications

References 43 publications

Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models

Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models

The Food Contaminant Deoxynivalenol Exacerbates the Genotoxicity of Gut Microbiota

Targeting colorectal cancer-associated bacteria: A new area of research for personalized treatments

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