Local production of reactive oxygen species drives vincristine-induced axon degeneration

Neurological side effects arising from chemotherapy, such as severe pain and cognitive impairment, are a major concern for cancer patients. These major side effects can lead to reduction or termination of chemotherapy medication in patients, negatively impacting their prognoses. With cancer survival...

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Published in:Cell death & disease 2023-12, Vol.14 (12), p.807-807, Article 807
Main Authors: Gomez-Deza, Jorge, Slavutsky, Anastasia L., Nebiyou, Matthew, Le Pichon, Claire E.
Format: Article
Language:English
Subjects:
13
13/106
13/62
14
14/35
14/63
631/378/1689
631/378/1934
631/378/87
82
82/58
Antibodies
Antioxidants - metabolism
Axons - metabolism
Biochemistry
Biomedical and Life Sciences
Cancer
Cancer therapies
Cell Biology
Cell Culture
Chemotherapy
Cognitive ability
Degeneration
Glutathione
Humans
Immunology
Life Sciences
Mitochondria
Molecular modelling
Neurons - metabolism
Neurotoxicity
Neurotoxicity Syndromes - pathology
Reactive oxygen species
Reactive Oxygen Species - metabolism
Side effects
Solid tumors
Vincristine
Vincristine - adverse effects
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creator Gomez-Deza, Jorge
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description Neurological side effects arising from chemotherapy, such as severe pain and cognitive impairment, are a major concern for cancer patients. These major side effects can lead to reduction or termination of chemotherapy medication in patients, negatively impacting their prognoses. With cancer survival rates improving dramatically, addressing side effects of cancer treatment has become pressing. Here, we use iPSC-derived human neurons to investigate the molecular mechanisms that lead to neurotoxicity induced by vincristine, a common chemotherapeutic used to treat solid tumors. Our results uncover a novel mechanism by which vincristine causes a local increase in mitochondrial proteins that produce reactive oxygen species (ROS) in the axon. Vincristine triggers a cascade of axon pathology, causing mitochondrial dysfunction that leads to elevated axonal ROS levels and SARM1-dependent axon degeneration. Importantly, we show that the neurotoxic effect of increased axonal ROS can be mitigated by the small molecule mitochondrial division inhibitor 1 (mdivi-1) and antioxidants glutathione and mitoquinone, identifying a novel therapeutic avenue to treat the neurological effects of chemotherapy.
doi_str_mv 10.1038/s41419-023-06227-8
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subjects 13
13/106
13/62
14
14/35
14/63
631/378/1689
631/378/1934
631/378/87
82
82/58
Antibodies
Antioxidants - metabolism
Axons - metabolism
Biochemistry
Biomedical and Life Sciences
Cancer
Cancer therapies
Cell Biology
Cell Culture
Chemotherapy
Cognitive ability
Degeneration
Glutathione
Humans
Immunology
Life Sciences
Mitochondria
Molecular modelling
Neurons - metabolism
Neurotoxicity
Neurotoxicity Syndromes - pathology
Reactive oxygen species
Reactive Oxygen Species - metabolism
Side effects
Solid tumors
Vincristine
Vincristine - adverse effects
title Local production of reactive oxygen species drives vincristine-induced axon degeneration
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