Neurotoxicity of cytarabine (Ara-C) in dorsal root ganglion neurons originates from impediment of mtDNA synthesis and compromise of mitochondrial function

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.

Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η

“…In contrast, we do not observe any Polδ-catalyzed base incorporation opposite the template AraC residue, similar to that is observed with other high-fidelity polymerases 16,18,29,30 . Thus, on the unmodified template in the presence of all dNTPs, Polδ extends ~44% of the primer strands (Fig.…”

Trifluoperazine an Antipsychotic Drug and Inhibitor of Mitochondrial Permeability Transition Protects Cytarabine and Ifosfamide-Induced Neurotoxicity

“…This study suggests that cytarabine neurotoxicity in neurons originates in mitochondria and continuous with oxidative stress [10]. Also, IFOS, a structural analog of cyclophosphamide, is an alkylating chemotherapy agent used for a wide range of solid and hematologic malignancies [10]. IFOS has been reported to have adverse neurological effects [11].…”

“…A recent study showed that cytarabine inhibits DNA polymerase γ and leads to reduction in mitochondrial DNA (mtDNA) content, ROS generation and oxidative damage in neurons. This study suggests that cytarabine neurotoxicity in neurons originates in mitochondria and continuous with oxidative stress [10]. Also, IFOS, a structural analog of cyclophosphamide, is an alkylating chemotherapy agent used for a wide range of solid and hematologic malignancies [10].…”

Hypoxia potentiates the capacity of melanoma cells to evade cisplatin and doxorubicin cytotoxicity via glycolytic shift

“…6). Cultures challenged with drugs under normoxic and hypoxic conditions were processed in parallel and XF24‐implemented sequential additions of mitochondrial effectors, oligomycin, FCCP, 2‐deoxyglucose (2DG), and antimycin A, served to determine the treatments signatures on respiratory parameters, as we previously described [16,26]. Under normoxic conditions, baseline OCR in YUMM1.7 was ~ 30% lower compared to B16F10 cells.…”

“…Oxygen consumption rates (OCR) were measured using XF24 extracellular flux analyzer (Seahorse, Agilent, Folsom, CA, USA) according to established protocols [23–25] and as we described [16,21,26]. B16F10 and YUMM1.7 cells were seeded in XF24 plates ([0.8‐1.2] × 10 4 /well), grown overnight, and treated as indicated.…”