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Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy. Mol Cell Neurosci 2018 01;86:65-71

Date

11/29/2017

Pubmed ID

29180229

Pubmed Central ID

PMC6996272

DOI

10.1016/j.mcn.2017.11.014

Scopus ID

2-s2.0-85036596177   16 Citations

Abstract

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.

Author List

Moruno-Manchon JF, Uzor NE, Kesler SR, Wefel JS, Townley DM, Nagaraja AS, Pradeep S, Mangala LS, Sood AK, Tsvetkov AS

Author

Sunila Pradeep PhD Assistant Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antibiotics, Antineoplastic
Cells, Cultured
Doxorubicin
Female
Frontal Lobe
Mice
Neurons
Oxidative Stress
Peroxisomes
Rats
Reactive Oxygen Species
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a