Drug-induced gene expression profile changes in relation to intestinal toxicity: State-of-the-art and new approaches

Rodrigues, Daniela; Souza, Terezinha de; Jennen, Danyel; Lemmens, Lieve; Kleinjans, Jos; Kok, Theo M. de

doi:10.1016/j.ctrv.2019.06.004

Cited by 17 publications

(12 citation statements)

References 81 publications

(170 reference statements)

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“…Only a few studies have established 5-FU mechanisms of toxicity at the level of transcriptomic responses in humans (Rodrigues et al 2019 ). Two of the most significantly altered DEGs found in SI organoids were previously reported, namely TYMS (Braun et al 2009 ) and EML2 (Del Rio et al 2007 ).…”

Section: Discussionmentioning

confidence: 99%

New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids

et al. 2021

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Abstract5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development.

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Section: Discussionmentioning

confidence: 99%

New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids

et al. 2021

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“…However, chemotherapeutics are always accompanied with intestinal adverse reactions including diarrhea, constipation and peptic ulcer due to their non-selection, megadose and long-course, which eventually lead to vicious malnutrition and cachexia, even shock and death 1 , 2 , 3 . It was reported that over 40% of chemotherapy patients suffer from intestinal toxicity in clinic, which has become an important reason for the interruption of therapy or withdrawal of approved chemotherapy agents 4 , 5 , 6 . However, unfortunately, there remains lack of clinically effective intervention targets and approach for the chemotherapeutics-induced intestinal injury 7 , 8 .…”

Section: Introductionmentioning

confidence: 99%

Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage

Wang

Zhang

et al. 2021

Acta Pharmaceutica Sinica B

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Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan (Trp)−kynurenine (KYN)−kynurenic acid (KA) axis metabolism. Mechanistically, chemotherapy-induced intestinal damage triggered the formation of an interleukin-6 (IL-6)−indoleamine 2,3-dioxygenase 1 (IDO1)−aryl hydrocarbon receptor (AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35 (GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic. This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.

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“…HCC is the fifth most common form of cancer type in the world [33][34][35][36]. The traditional treatment strategy for HCC is radical resection, but the rate of recurrence is very high, and the 5-year survival rate is low [37][38][39][40][41]. Thus, the 11 International Journal of Genomics prognosis of HCC is still unsatisfactory.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-497-5p Is Downregulated in Hepatocellular Carcinoma and Associated with Tumorigenesis and Poor Prognosis in Patients

Jiang

Liu

et al. 2021

International Journal of Genomics

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Background. MicroRNAs (miRNAs) have been demonstrated to exhibit important regulatory roles in multiple malignancies, including hepatocellular carcinoma (HCC). hsa-miR-497-5p was reported to involve in cancer progression and poor prognosis in many kinds of tumors. However, the expression and its clinical significance of hsa-miR-497-5p in HCC remain unclear. Methods. In the present study, we investigated the expression of hsa-miR-497-5p in HCC and analyzed the correction of clinical features with prognosis. The expression levels of hsa-miR-497-5p and potential target genes were analyzed in HCC and adjacent noncancerous tissues using The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze hsa-miR-497-5p levels in 328 HCC tissues and 30 paired adjacent noncancer tissues. Overall survival (OS) and progression-free survival (PFS) of patients with HCC were assessed using the Kaplan-Meier method and the log-rank test. Results. The hsa-miR-497-5p expression levels were decreased, and its target genes ACTG1, CSNK1D, PPP1CC, and BIRC5 were upregulated in HCC tissues compared with normal tissues. Lower levels of hsa-miR-497-5p expression and higher levels of the four target genes were significantly associated with higher tumor diameter. Moreover, patients with lower hsa-miR-497-5p expression and higher target genes levels had shorter OS. Conclusion. The expression levels of hsa-miR-497-5p may play an important regulatory role in HCC and are closely correlated with HCC progression and poor prognosis in patients. The hsa-miR-497-5p may be a specific therapeutic target for the treatment of HCC.

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Drug-induced gene expression profile changes in relation to intestinal toxicity: State-of-the-art and new approaches

Cited by 17 publications

References 81 publications

New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids

New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids

Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage

MicroRNA-497-5p Is Downregulated in Hepatocellular Carcinoma and Associated with Tumorigenesis and Poor Prognosis in Patients

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