ArticleFree radical biology & medicine2018
Neurotoxicity of cytarabine (Ara-C) in dorsal root ganglion neurons originates from impediment of mtDNA synthesis and compromise of mitochondrial function.
Article in Free radical biology & medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Chemotherapy-induced oxidative injury in pediatric acute lymphoblastic leukemia: The role of N-acetylcysteine (Review).Biomedical reports · 2026Review
- Protective effects of morin and propolis against cytarabine-induced neurotoxicity: a multi-biomarker approach.Open life sciences · 2026Article
- The synergistic effect of 2-deoxy-D-glucose and cytarabine on mitochondria of stem-like cells derived from KG1-a.Leukemia research reports · 2025Article
- Oxygen matters: Unraveling the role of oxygen in the neuronal response to cisplatin.Journal of the peripheral nervous system : JPNS · 2024Article
- Human sensory-like neuron cultivation-An optimized protocol.Frontiers in neuroscience · 2024Article
- Activation of the STING pathway induces peripheral sensitization via neuroinflammation in a rat model of bone cancer pain.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2023Article
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- LIS1 and NDEL1 Regulate Axonal Trafficking of Mitochondria in Mature Neurons.Frontiers in molecular neuroscience · 2022Article
- Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.Blood advances · 2021Article
- Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.EMBO reports · 2021Article
- Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Hypoxia potentiates the capacity of melanoma cells to evade cisplatin and doxorubicin cytotoxicity via glycolytic shift.FEBS open bio · 2020Article
- Modeling chemotherapy induced peripheral neuropathy (CIPN) in vitro: Prospects and limitations.Experimental neurology · 2020Review
- Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy.Frontiers in oncology · 2020Article
- Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η.Scientific reports · 2019Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Peripheral Nervous System (PNS) neurotoxicity caused by cancer drugs hinders attainment of chemotherapy goals. Due to leakiness of the blood nerve barrier, circulating chemotherapeutic drugs reach PNS neurons and adversely affect their function. Chemotherapeutic drugs are designed to target dividing cancer cells and mechanisms underlying their toxicity in postmitotic neurons remain to be fully clarified. The objective of this work was to elucidate progression of events triggered by antimitotic drugs in postmitotic neurons. For proof of mechanism study, we chose cytarabine (ara-C), an antimetabolite used in treatment of hematological cancers. Ara-C is a cytosine analog that terminates DNA synthesis. To investigate how ara-C affects postmitotic neurons, which replicate mitochondrial but not genomic DNA, we adapted a model of Dorsal Root Ganglion (DRG) neurons. We showed that DNA polymerase γ, which is responsible for mtDNA synthesis, is inhibited by ara-C and that sublethal ara-C exposure of DRG neurons leads to reduction in mtDNA content, ROS generation, oxidative mtDNA damage formation, compromised mitochondrial respiration and diminution of NADPH and GSH stores, as well as, activation of the DNA damage response. Hence, it is plausible that in ara-C exposed DRG neurons, ROS amplified by the high mitochondrial content shifts from physiologic to pathologic levels signaling stress to the nucleus. Combined, the findings suggest that ara-C neurotoxicity in DRG neurons originates in mitochondria and that continuous mtDNA synthesis and reliance on oxidative phosphorylation for energy needs sensitize the highly metabolic neurons to injury by mtDNA synthesis terminating cancer drugs.
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