Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy
| Autor: | Andrey S. Tsvetkov, Debra M. Townley, Sunila Pradeep, Jose F. Moruno-Manchon, Shelli R. Kesler, Lingegowda S. Mangala, Archana S. Nagaraja, Anil K. Sood, Jeffrey S. Wefel, Ndidi Ese Uzor |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Senescence Biology medicine.disease_cause Article Mice 03 medical and health sciences Cellular and Molecular Neuroscience Peroxisomes polycyclic compounds medicine Animals Doxorubicin Molecular Biology Cells Cultured Neurons chemistry.chemical_classification Reactive oxygen species Antibiotics Antineoplastic Autophagy Neurotoxicity Cell Biology Peroxisome medicine.disease Frontal Lobe Rats Cell biology Oxidative Stress 030104 developmental biology chemistry Biochemistry TFEB Female Reactive Oxygen Species Oxidative stress medicine.drug |
| Zdroj: | Molecular and Cellular Neuroscience. 86:65-71 |
| ISSN: | 1044-7431 |
| DOI: | 10.1016/j.mcn.2017.11.014 |
| Popis: | Doxorubicin, a commonly used anti-neoplastic agent, causes severe neurotoxicity. Doxorubicin promotes thinning of the brain cortex and accelerates brain aging, leading to cognitive impairment. Oxidative stress induced by doxorubicin contributes to cellular damage. In addition to mitochondria, peroxisomes also generate reactive oxygen species (ROS) and promote cell senescence. Here, we investigated if doxorubicin affects peroxisomal homeostasis in neurons. We demonstrate that the number of peroxisomes is increased in doxorubicin-treated neurons and in the brains of mice which underwent doxorubicin-based chemotherapy. Pexophagy, the specific autophagy of peroxisomes, is downregulated in neurons, and peroxisomes produce more ROS. 2-hydroxypropyl-β-cyclodextrin (HPβCD), an activator of the transcription factor TFEB, which regulates expression of genes involved in autophagy and lysosome function, mitigates damage of pexophagy and decreases ROS production induced by doxorubicin. We conclude that peroxisome-associated oxidative stress induced by doxorubicin may contribute to neurotoxicity, cognitive dysfunction, and accelerated brain aging in cancer patients and survivors. Peroxisomes might be a valuable new target for mitigating neuronal damage caused by chemotherapy drugs and for slowing down brain aging in general. |
| Databáze: | OpenAIRE |
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