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

Markus Leo,Tim Hagenacker,Ulrike B Hendgen-Cotta,Tienush Rassaf,Christoph Kleinschnitz,Patricia Küsterarent,Andrea Kutritz,Linda-Isabell Schmitt

doi:10.3390/ijms21228636

Abstract

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 µM 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 µM 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.

Highlights

Cytostatic drugs as cis- and oxaliplatin are still common in tumor therapy today
When cultured dorsal root ganglion (DRG) neurons were exposed to 0.1 μM, 1 μM, or 10 μM of cisplatin no change in viability was observed after 24 h (0.1 μM: 141850 ± 2184.98 RLU; 1 μM: 136350 ± 1619.92 RLU; 10 μM: 136650 ± 5899.78 RLU), compared to untreated control cells (135700 ± 1603.12)
When cultured DRG neurons were treated with different concentrations of these chemotherapeutics, no change in cell viability was observed when cells were treated with 0.1 μM, 1 μM, or 10 μM after 24 h

Summary

Introduction

Cytostatic drugs as cis- and oxaliplatin are still common in tumor therapy today. While cisplatin is used for the treatment of lung, testicular, or ovarian cancer, oxaliplatin is majorly used for colorectal cancer [1,2,3,4]. DRG neurons are cells of the peripheral nervous system responsible for the detection of noxious (potentially damaging) stimuli These neurons express a specialized setup of receptors and channels that can be activated by mechanical, thermal, or chemical stimuli and contribute to typical symptoms of CIPN as hyperalgesia, allodynia, or numbness Several of these receptors or channels such as voltage-gated calcium channels or type 1 lysophosphatidic acid (LPA1) receptors are discussed as playing a critical role in the induction of polyneuropathies or neuropathic pain in different models Prior studies suggest TRPA1 as a potential target for pain therapy [23]

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