Modulation by Ozone Therapy of Oxidative Stress in Chemotherapy-Induced Peripheral Neuropathy: The Background for a Randomized Clinical Trial

Bernardino Clavo, Gregorio Martínez-Sánchez, Francisco Rodríguez-Esparragón, Delvys Rodríguez-Abreu, Saray Galván, David Aguiar-Bujanda, Juan A Díaz-Garrido, Silvia Cañas, Laura B Torres-Mata, Himar Fabelo, Teresa Téllez, Norberto Santana-Rodríguez, Leandro Fernández-Pérez, Gustavo Marrero-Callico, Bernardino Clavo, Gregorio Martínez-Sánchez, Francisco Rodríguez-Esparragón, Delvys Rodríguez-Abreu, Saray Galván, David Aguiar-Bujanda, Juan A Díaz-Garrido, Silvia Cañas, Laura B Torres-Mata, Himar Fabelo, Teresa Téllez, Norberto Santana-Rodríguez, Leandro Fernández-Pérez, Gustavo Marrero-Callico

Abstract

(1) Background: Chemotherapy-induced peripheral neuropathy (CIPN) decreases the quality of life of patients and can lead to a dose reduction and/or the interruption of chemotherapy treatment, limiting its effectiveness. Potential pathophysiological mechanisms involved in the pathogenesis of CIPN include chronic oxidative stress and subsequent increase in free radicals and proinflammatory cytokines. Approaches for the treatment of CIPN are highly limited in their number and efficacy, although several antioxidant-based therapies have been tried. On the other hand, ozone therapy can induce an adaptive antioxidant and anti-inflammatory response, which could be potentially useful in the management of CIPN. (2) Methods: The aims of this works are: (a) to summarize the potential mechanisms that could induce CIPN by the most relevant drugs (platinum, taxanes, vinca alkaloids, and bortezomib), with particular focus on the role of oxidative stress; (b) to summarize the current situation of prophylactic and treatment approaches; (c) to describe the action mechanisms of ozone therapy to modify oxidative stress and inflammation with its potential repercussions for CIPN; (d) to describe related experimental and clinical reports with ozone therapy in chemo-induced neurologic symptoms and CIPN; and (e) to show the main details about an ongoing focused clinical trial. (3) Results: A wide background relating to the mechanisms of action and a small number of experimental and clinical reports suggest that ozone therapy could be useful to prevent or improve CIPN. (4) Conclusions: Currently, there are no clinically relevant approaches for the prevention and treatment of stablished CIPN. The potential role of ozone therapy in this syndrome merits further research. Randomized controlled trials are ongoing.

Keywords: antioxidants; cancer treatment; chemotherapy-induced peripheral neuropathy; chemotherapy-induced side effects; chemotherapy-induced toxicity; free radicals; oxaliplatin; oxidative stress; ozone therapy; randomized clinical trial.

Conflict of interest statement

The authors declare no other conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. All authors confirm that they had full access to all the data in the study and accept responsibility to submit for publication.

Figures

Figure 1
Figure 1
Hypothetic effects of ozone mediators on Nrf2 and NfκB pathways. After administration, ozone reacts with biomolecules, including polyunsaturated fatty acids (PUFA) or plasma membrane, producing hydroperoxides, aldehydes, and H2O2 [60]. H2O2 can enter the cytoplasm of mononuclear cells and modulate nuclear factor NF-κB/Nrf2 pathways. Casein kinase 2 (CK2), CREB binding protein (CBP), cyclooxygenase-2 (COX-2), Electrophile-responsive elements (EpRE), Epidermal growth factor receptor (EGFr), Heme-oxygenase-1 (HO-1), Histone deacetylase 3 (HDAC3), Inducible nitric oxide synthase (iNOS), Interleukin-1β (IL-1 β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Intracellular adhesion molecule (ICAM), IκB kinase (IKK), Kelch-like ECH-associated protein 1 (Keap1), Nuclear erythroid 2 related factor 2 (Nrf2), Phospholipase A2 (PLA2), Tumor necrosis factor-α (TNF-α).

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