Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy

Jose F. Moruno-Manchon, Ndidi Ese Uzor, Shelli R. Kesler, Jeffrey S. Wefel, Debra M. Townley, Archana Sidalaghatta Nagaraja, Sunila Pradeep, Lingegowda S. Mangala, Anil K. Sood, Andrey S. Tsvetkov

Research output: Contribution to journalArticlepeer-review

34 Scopus 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.

Original languageEnglish (US)
Pages (from-to)65-71
Number of pages7
JournalMolecular and Cellular Neuroscience
Volume86
DOIs
StatePublished - Jan 2018

Keywords

  • Brain aging
  • Chemotherapy
  • Doxorubicin
  • Peroxisomes

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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