Platinum-Based Drugs Cause Mitochondrial Dysfunction In Cultured Dorsal Root Ganglion Neurons

Cisplatin and oxaliplatin are treatment options for a variety of cancer types. While highly efficient in killing cancer cells, both chemotherapeutics cause severe side effects, e.g., peripheral neuropathies. Using a cell viability assay, a mitochondrial stress assay, and live-cell imaging, the effects of cis- or oxaliplatin on the mitochondrial function, reactive oxygen species (ROS) production, and mitochondrial and cytosolic calcium concentration of transient receptor potential ankyrin 1 (TRPA1)- or vanilloid 1 (TRPV1)-positive dorsal root ganglion (DRG) neurons of adult Wistar rats were determined. Mitochondrial functions were impaired after exposure to cis- or oxaliplatin by mitochondrial respiratory chain complex I-III inhibition. The basal respiration, spare respiratory capacity, and the adenosine triphosphate (ATP)-linked respiration were decreased after exposure to 10 mu M cis- or oxaliplatin. The ROS production showed an immediate increase, and after reaching the peak, ROS production dropped. Calcium imaging showed an increase in the cytosolic calcium concentration during exposure to 10 mu M cis- or oxaliplatin in TRPA1- or TRPV1-positive DRG neurons while the mitochondrial calcium concentration continuously decreased. Our data demonstrate a significant effect of cis- and oxaliplatin on mitochondrial function as an early event of platinum-based drug exposure, suggesting mitochondria as a potential target for preventing chemotherapy-induced neuropathy.