Key result
Doxorubicin exposure in 3D small intestine and colon organoids primarily affected the cell cycle, p53 signalling pathway, and oxidative stress, with distinct metabolic responses between tissue types.
Why the study?
Doxorubicin causes severe intestinal side effects that can interrupt chemotherapy, but the molecular mechanisms associated with its intestinal toxicity have been poorly explored.
Does doxorubicin exposure affect transcriptomic responses, viability, and apoptosis in 3D human intestinal organoids?
Does doxorubicin exposure affect transcriptomic responses, viability, and apoptosis in 3D human intestinal organoids?
Doxorubicin induces distinct transcriptomic responses in human small intestine and colon organoids, primarily affecting cell cycle, p53 signaling, and oxidative stress pathways.
Answers are grounded in this paper and cite their sources.
May inform mitigation of doxorubicin GI toxicity; hypothesis-generating for clinical translation pending patient validation.
Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity.
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Rodrigues et al. (2022) studied Doxorubicin-induced intestinal toxicity. Doxorubicin was evaluated on Transcriptomic responses in relation to viability and apoptosis. Doxorubicin exposure in 3D small intestine and colon organoids primarily affected the cell cycle, p53 signalling pathway, and oxidative stress, with distinct metabolic responses between tissue types.
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