Abstract
In the most recent decades, oxaliplatin has been used as a chemotherapeutic agent for colorectal cancer and other malignancies as well. Oxaliplatin interferes with tumor growth predominantly exerting its action in DNA synthesis inhibition by the formation of DNA-platinum adducts that, in turn, leads to cancer cell death. On the other hand, unfortunately, this interaction leads to a plethora of systemic side effects, including those affecting the peripheral and central nervous system. Oxaliplatin therapy has been associated with acute and chronic neuropathic pain that induces physicians to reduce the dose of medication or discontinue treatment. Recently, the capability of oxaliplatin to alter the genetic and epigenetic profiles of the nervous cells has been documented, and the understanding of gene expression and transcriptional changes may help to find new putative treatments for neuropathy. The present article is aimed to review the effects of oxaliplatin on genetic and epigenetic mechanisms to better understand how to ameliorate neuropathic pain in order to enhance the anti-cancer potential and improve patients’ quality of life.
Highlights
The Anti-cancer Features of OxaliplatinIn the last decades, despite early cancer diagnosis, cancer deaths rapidly increased (Kanavos, 2006)
These results suggest that reactive oxygen species (ROS) generation and mitochondrial impairment are early events in the oxaliplatin-triggered signaling pathway that results in the onset of neuropathy
In view of these fascinating scenarios, it has been recently hypothesized that the pivotal role of single nucleotide polymorphisms (SNPs) affects the gene coding for oxaliplatin transporters
Summary
Despite early cancer diagnosis, cancer deaths rapidly increased (Kanavos, 2006). The most relevant mechanism that trigger neuropathic pain (extensively reviewed by Kanat et al, 2017), is the binding of oxaliplatin to the mitochondrial DNA of sensory neurons, causing their death This oxaliplatin-dependent neuronal loss accounts for the persistence of symptoms for up to years following treatment discontinuation (Kokotis et al, 2016). The expression of OCT-type transporters by sensory neurons of the dorsal root ganglia (DRG) (Fujita et al, 2019) demonstrates the accumulation of the chemotherapy mainly in these cell type, and that this event could trigger a peripheral neurotoxicity These data were corroborated by other results demonstrating the oxaliplatin-dependent detrimental effect on DRG neurons causing a reduced volume of the neuronal soma and an increase in the number of multinucleated neuronal nuclei (Di Cesare Mannelli et al, 2017). These effects are in accordance with ex vivo experiments carried
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