TY - JOUR
T1 - Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy
AU - Moruno-Manchon, Jose F.
AU - Uzor, Ndidi Ese
AU - Kesler, Shelli R.
AU - Wefel, Jeffrey S.
AU - Townley, Debra M.
AU - Nagaraja, Archana Sidalaghatta
AU - Pradeep, Sunila
AU - Mangala, Lingegowda S.
AU - Sood, Anil K.
AU - Tsvetkov, Andrey S.
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - Brain aging
KW - Chemotherapy
KW - Doxorubicin
KW - Peroxisomes
UR - http://www.scopus.com/inward/record.url?scp=85036596177&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85036596177&partnerID=8YFLogxK
U2 - 10.1016/j.mcn.2017.11.014
DO - 10.1016/j.mcn.2017.11.014
M3 - Article
C2 - 29180229
AN - SCOPUS:85036596177
SN - 1044-7431
VL - 86
SP - 65
EP - 71
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
ER -