Modulation of Oxidative Stress by Ozone Therapy in the Prevention and Treatment of Chemotherapy-Induced Toxicity: Review and Prospects

Bernardino Clavo, Francisco Rodríguez-Esparragón, Delvys Rodríguez-Abreu, Gregorio Martínez-Sánchez, Pedro Llontop, David Aguiar-Bujanda, Leandro Fernández-Pérez, Norberto Santana-Rodríguez, Bernardino Clavo, Francisco Rodríguez-Esparragón, Delvys Rodríguez-Abreu, Gregorio Martínez-Sánchez, Pedro Llontop, David Aguiar-Bujanda, Leandro Fernández-Pérez, Norberto Santana-Rodríguez

Abstract

(1) Background: Cancer is one of the leading causes of mortality worldwide. Radiotherapy and chemotherapy attempt to kill tumor cells by different mechanisms mediated by an intracellular increase of free radicals. However, free radicals can also increase in healthy cells and lead to oxidative stress, resulting in further damage to healthy tissues. Approaches to prevent or treat many of these side effects are limited. Ozone therapy can induce a controlled oxidative stress able to stimulate an adaptive antioxidant response in healthy tissue. This review describes the studies using ozone therapy to prevent and/or treat chemotherapy-induced toxicity, and how its effect is linked to a modification of free radicals and antioxidants. (2) Methods: This review encompasses a total of 13 peer-reviewed original articles (most of them with assessment of oxidative stress parameters) and some related works. It is mainly focused on four drugs: Cisplatin, Methotrexate, Doxorubicin, and Bleomycin. (3) Results: In experimental models and the few existing clinical studies, modulation of free radicals and antioxidants by ozone therapy was associated with decreased chemotherapy-induced toxicity. (4) Conclusions: The potential role of ozone therapy in the management of chemotherapy-induced toxicity merits further research. Randomized controlled trials are ongoing.

Keywords: antioxidants; bleomycin; cancer treatment; chemotherapy-induced toxicity; cisplatin; doxorubicin; free radicals; methotrexate; oxidative stress; ozone therapy.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representation of the interaction with the crosstalk between the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB) pathways and the role of ozone. HO-1, haem-oxygenase-1; ARE, antioxidant response element; Keap1, Kelch-like ECH-associated protein 1; IKK: IκB kinase; CBP: CREB binding protein; HDAC3: histone deacetylase 3. Nrf2: nuclear erythroid 2 related factor 2; NF-κB: nuclear factor kappa light chain enhancer of B cell; LPS: lipopolysaccharide; O3: ozone.
Figure 2
Figure 2
Schemes of results obtained in the experimental studies using systemic ozone therapy (rectal or intraperitoneal) using chemotherapy drugs. (Left and Middle): “Oxidative stress markers” (MDA: malondialdehyde, TBARS: thiobarbituric acid-reactive substances) and “Tissue damage markers” (creatinine, pro-BNP: pro-brain natriuretic peptide) increased largely and significantly with chemotherapy. The increase was significantly lower in rats with chemotherapy + ozone therapy. (Middle): levels of “Antioxidants” (GSH: glutathione, SOD: superoxide dismutase, CAT: catalase and GSH-GPx: glutathione peroxidase) decreased in chemotherapy group whereas those contents were closer to the control group in rats treated with chemotherapy + ozone therapy. All differences were statistically significant.
Figure 3
Figure 3
The redox status of patients with rheumatoid arthritis in (a): Methotrexate (MTX) and (b): “MTX + ozone” groups at the end of the study. (A) Protective redox markers, (B) Injury redox markers. The units of each marker are: SOD (superoxide dismutase, U/mL/min) and CAT (catalase, U/L/min) activities, GSH (reduced glutathione, µM), NO (nitric oxide, µM), AOPP (advanced oxidation protein products, µM), TH (total hydroperoxides, µM), MDA (malondialdehyde, µM). Data represent the mean ± S.E.M. of each group. Data analysis for each group was made by t-test. All differences between MTX vs. MTX + ozone groups were statistically significant, p < 0.05. From Ref. [56], with permission.
Figure 4
Figure 4
Topical ozone treatment in a patient with skin necrosis after Doxorubicin extravasation. A 61-year old patient under treatment for a stage IIIA multiple myeloma suffered a skin necrosis secondary to Doxorubicin (DOX) extravasation in the left elbow flexure. Because adverse evolution with conservative management, a muscle flap with a cutaneous graft was required (by the Department of Plastic Surgery). A second surgery was planned because of a loss of tissue in the distal area of the graft. (Left): Picture at the 9th session of local ozone therapy (wound size 25 × 15 mm). Black arrows and dotted lines show the limits of the wound at the commencement of ozone therapy (wound size 60 × 30 mm). (Right): Picture at the end of local ozone therapy, after 20 sessions. The planned second graft was avoided.

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Source: PubMed

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