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Review

Oxyhydrogen Gas: A Promising Therapeutic Approach for Lung, Breast and Colorectal Cancer

by
Grace Russell
1,2,* and
Alexander Nenov
2
1
Applied Biomedical Research Consultant, Weston-Super-Mare BS23 1EF, UK
2
Water Fuel Engineering, Wakefield WF1 5QY, UK
*
Author to whom correspondence should be addressed.
Oxygen 2024, 4(3), 338-350; https://doi.org/10.3390/oxygen4030020
Submission received: 14 June 2024 / Revised: 5 August 2024 / Accepted: 21 August 2024 / Published: 26 August 2024
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Abstract

:
Cancer remains one of the leading causes of death despite advancements in research and treatment, with traditional therapies often causing significant side effects and resistance. Oxyhydrogen gas, a mixture of 66% molecular hydrogen (H2) and 33% molecular oxygen (O2) has shown exceptional promise as a novel therapeutic agent due to its ability to modulate oxidative stress, inflammation, and apoptosis. H2, a key component of oxyhydrogen gas, neutralises reactive oxygen and nitrogen species, enhancing existing treatments and reducing harmful oxidative states in cancer cells. H2 also lowers proinflammatory mediators including chemokines, cytokines, and interleukins, inhibiting cancer cell proliferation and boosting the effectiveness of conventional therapies. Additionally, hydrogen can induce apoptosis in cancer cells by modulating pathways such as MAPK and inhibiting the PI3K/Akt phosphorylation cascade. Preclinical and clinical evidence supports oxyhydrogen gas’s potential in treating various cancers. In lung cancer models, it inhibits cell proliferation, induces apoptosis, and enhances chemotherapy sensitivity. Similar results have been observed in breast cancer, where patients reported improved quality of life. In colorectal cancer, oxyhydrogen gas suppresses tumour growth, induces apoptosis, and improves intestinal microflora dysbiosis. The unique properties of oxyhydrogen gas make it a promising adjunctive or standalone cancer treatment. However, further research is needed to understand H2s’ mechanisms, optimise treatment protocols, and evaluate long-term safety and efficacy in human patients.

1. Introduction

Cancer is a complex and multifaceted disease characterised by uncontrolled cell growth, invasion of surrounding tissues, and metastasis to distant organs. Despite significant advancements in cancer research and treatment modalities, the burden of cancer continues to increase globally [1]. Conventional cancer therapies such as chemotherapy, radiation therapy, and surgery have limitations, including toxic side effects, drug resistance, and damage to healthy tissues [2]. Therefore, there is a critical need for the development of novel and more effective treatment strategies for cancer.
Oxyhydrogen gas, a mixture of molecular hydrogen (66% H2) and molecular oxygen (33% O2) gases, has recently emerged as a promising therapeutic agent in the field of oncology. This novel approach leverages the unique chemical properties of molecular hydrogen and its potential to modulate cellular oxidative stress, inflammation, and apoptosis [3], all of which are critical processes in carcinogenesis, progression and resistance to cancer treatments [4]. Additionally, H2 has been investigated for its potential to influence immune responses, primarily through its interaction with the mitochondrial electron transport chain [5].
The therapeutic potential of oxyhydrogen gas may be attributed to its modulatory properties, which potentially enable this therapy to reduce the damage caused by reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS/RNS are chemically reactive molecules containing oxygen or nitrogen, respectively, that are byproducts of cellular metabolism. Primarily produced in the mitochondria, ROS/RNS have major roles in cell signaling and, consequently, cellular homeostasis [6]. Such reactive biological gases have a complex role in cancer, acting as both promoters and inhibitors of tumour progression depending on the type and stage of the tumour [2]. For example, an overproduction of ROS/RNS can contribute to their proliferative and metastatic capabilities of cancer cells [7,8] or induce regulated cell death (apoptosis). Excessive ROS levels can also induce DNA mutations and genomic instability, and activate pro-survival signaling pathways. Preliminary studies suggest that hydrogen-containing therapies, including oxyhydrogen gas, may also have anti-tumour effects [9,10,11]. However, this research is still in its initial phases and more comprehensive studies are needed to fully understand the efficacy and mechanisms of oxyhydrogen therapy in cancer treatment.

2. Oxyhydrogen Therapies

Oxyhydrogen gas (also known as Brown’s gas) has unique properties that make it an attractive candidate for cancer therapy. This stoichiometric mixture of gases has been shown to exhibit antioxidant, anti-inflammatory, and anti-tumour effects, making it a promising approach for cancer management [11,12,13,14,15,16,17,18,19].
Generated through the electrolysis of water, oxyhydrogen has shown potential as an effective anti-inflammatory and antioxidant gas. For example, the therapeutic potential of oxyhydrogen gas has been explored in the context of Epstein–Barr Virus (EBV)-immortalised B-lymphoblastoid cells [11]. These cells are key to the adaptive immune response and are essential for presenting tumour-associated antigens to various types of T-cells. Briefly, the study aimed to assess the effects of direct infusion of oxyhydrogen gas on the replicative capacity of malignant immune cells, the results indicating a trend of replicative inhibition of these cells with a single oxyhydrogen treatment [11]. Further research has demonstrated the physiological tolerance and effectiveness of oxyhydrogen therapies in a range of small scale trials, including those for such conditions as cancer, cardiovascular disease, and chronic obstructive pulmonary disease [12,13,14,15].
The antioxidant properties of oxyhydrogen gas are of particular interest in the context of cancer therapy. ROS, such as superoxide radicals (O2•−) and hydrogen peroxide (H2O2), are generated as byproducts of cellular metabolism and play a crucial role in cancer development and progression [20]. However, the anti-tumour effects of oxyhydrogen gas extend beyond its antioxidant and anti-inflammatory properties. Studies have demonstrated that oxyhydrogen gas can directly inhibit cancer cell proliferation, induce apoptosis, and suppress tumour growth in various cancer models. For example, research conducted by Iio et al. (2013) investigated the effect of molecular hydrogen on human liver hepatocellular carcinoma cell lines and found that oxygen/hydrogen treatment (75% H2, 20% O2 and 5% CO2) reduced lipid accumulation in vitro [21]. Similarly, studies on animal models have shown that oxyhydrogen gas administration can suppress tumour growth and improve survival rates in models with breast cancer [22], lung cancer [23], and colorectal cancer [24]. Anotherstudy conducted by Lee et al. (2012), investigated the use of inhaled hydrogen gas therapy for the prevention of testicular ischemia/reperfusion injury in rats. The study demonstrated that hydrogen gas inhalation (2% H2) reduced oxidative stress and mitigated tissue damage, suggesting its potential as a cytoprotective agent in cancer patients undergoing radiation therapy or chemotherapy [25].
Overall, the unique properties of oxyhydrogen gas make it a promising therapeutic approach for cancer treatment. Its antioxidant, anti-inflammatory, and anti-tumour effects have been demonstrated in preclinical studies [9,10,11,16,17,18,19,26] and in human pilot trials [12,13,14,15,27], suggesting its potential as an adjunctive therapy or standalone treatment for various types of cancer. However, further research is needed to elucidate the underlying mechanisms of action, optimise treatment protocols, and evaluate long-term safety and efficacy in human cancer patients. The following sections explore the current research on hydrogen and oxyhydrogen gases as a treatment for the three most prominent types of cancer, highlighting their potential benefits and possible mechanisms of action.

3. Mechanisms of Action: Oxygen

Oxygen plays a complex role in cancer growth and progression, and its effects can vary depending on the carcinogenic microenvironment [28]. Generally, oxygen is essential for normal cellular function and is involved in various cellular processes, including energy production (via oxidative phosphorylation) and, subsequently, DNA repair mechanisms [29,30]. However, in the context of cancer, the relationship between oxygen and tumour growth is multifaceted. The tumour microenvironment is dynamic and heterogeneous, with varying levels of oxygenation occurring within different regions of the tumour. This heterogeneity influences the response of cancer cells to oxygen and contributes to tumour progression and treatment resistance [31]. On one hand, oxygen is crucial for the growth and survival of most cells, including cancer cells. On the other, the detrimental effects of oxygen in malignant cells and tissues include increased levels of ROS; promotion of angiogenesis, a phenomenon essential for delivering nutrients and oxygen to cells and tissue structures (including tumours); and supporting tumour growth and progression by providing necessary resources to cancer cells [32]. Furthermore, solid tumours often develop regions of low oxygen concentration, or hypoxia, due to inadequate blood supply.
Hypoxic conditions can lead to the activation of survival mechanisms in cancer cells, including altered metabolism and resistance to therapy [33]. Hypoxia has been associated with aggressive tumour behaviour and poor treatment outcomes as hypoxic regions of tumours are often resistant to conventional cancer therapies, such as chemotherapy and radiation therapy. This can lead to treatment failure and disease recurrence [34]. Alternatively, normoxia can promote the proliferation and metabolism of cancer cells, enabling tumour growth and progression [35], as can hyperoxia, an excess of oxygen [36]. In such cases hyperoxia induces oxidative stress, leading to DNA damage, mitochondrial dysfunction, and ultimately, apoptosis in cancer cells.
Oxidative stress acts as a potent catalyst in transforming normal cells into cancerous phenotypes, primarily by compromising genomic integrity. Elevated levels of ROS interact with cellular macromolecules like DNA, RNA, and proteins [37]. For example, ROS generated during normal cellular metabolism can directly damage DNA by causing mutations and lesions, with oxygen radicals adhering to nucleotide bases, an action that can lead to genetic alterations which may initiate carcinogenesis [32]. Moreover, ROS modulate intracellular signalling pathways, affecting central cellular parameters such as the redox status, apoptosis, DNA repair mechanisms, and cellular proliferation [38]. Dysregulation of these pathways can lead to uncontrolled cell growth and evasion of cell death, hallmark features of cancer development.
Oxygen is essential for life, but its reactivity necessitates a delicate balance. Understanding the dichotomy of oxygen in cancer is essential for developing effective therapeutic strategies. While oxygen is necessary for normal cell function and can induce cell death in cancer cells under certain conditions, hypoxia and oxidative stress contribute to tumour progression and therapy resistance [31]. Targeting the oxygen-dependent pathways in cancer cells represents a promising approach for improving treatment outcomes and overcoming resistance. However, the role of oxygen in the anti-tumour effects of oxyhydrogen administration is unclear, and, as yet, no direct comparable studies regarding the effects of pure H2 and oxyhydrogen have been established.

4. Mechanisms of Action: Hydrogen

Atomic hydrogen (H) is the first element of the periodic table and constitutes approximately 75% of the universe’s elemental mass. Under natural conditions, however, hydrogen gas comprises of two atoms, formulating the diatomic molecule H2 (molecular weight: 2.016 g/mol) [39]. As the Earth’s early atmosphere was likely suffused with such reducing gases as carbon monoxide (CO), hydrogen (H2) and methane (CH4), it has been surmised that the ability to utilise iron-(Fe) induced catalysis of H2 as a means of supplying electrons and protons used for energy production, evolved billions of years ago [40]. From an evolutionary standpoint, it is likely that H2 may have been one of the first reducing agents exploited in early forms of microbial energy metabolism [41,42], which may explain the ubiquity of hydrogenase enzymes across the domains of life. In humans and mammals, H2 is produced solely by the metabolism of carbohydrate nutriments by intestinal microorganisms (e.g., Clostridia and Coliform), where H2 formation results primarily through the oxidation of pyruvate, formate, or reduced pyridine nucleotides (i.e., nicotinamide adenine dinucleotide/flavin adenine dinucleotide (NAD+/FAD), accordingly) [43]. Consequently, H2 is demonstrated to influence acid-based redox chemistry within cells.
Molecular hydrogen serves not only as an antioxidant by directly inhibiting ROS/RNS oxidation but also plays a documented role in activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nrf2 is a transcription factor associated with the antioxidant response element, a cis-acting regulatory sequencethat promotes the expression of antioxidant genes [44]. Consequently, hydrogen can enhance the expression of endogenous antioxidant enzymes, including catalase (CAT), glutathione peroxidase (GPx), haem oxygenase (e.g., HO-1), and superoxide dismutase (SOD) [45]. Importantly, such enzymes are responsible for neutralising such harmful substances as hydrogen peroxide and reducing the physiological damage caused by such ROS as the hydroxyl radical [46].
Aside from its antioxidant properties, hydrogen is recognised for its anti-inflammatory effects, reducing the expression of proinflammatory mediators such as chemokines (e.g., CXCL15), cytokines (e.g., TNF-α), interleukins (e.g., IL-4, IL-6), and transcription factors (e.g., the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)) [47]. This is particularly significant in the context of cancer development, where the immune system can either destroy nascent cancer cells or promote their growth into tumours. Thus, therapies targeting immune responses and enhancing immunity show promise in treating various malignancies.
As a result of its neutral charge, non-polarity, and low molecular weight, H2 gas is highly diffusible in biological systems, negotiating passage through the blood/brain, placental and testes barriers, the lipid membranes, cytosolic fluid, and into the cellular compartments including organelles, relatively unobstructed [48]. This property of H2 is deemed profoundly favourable, as conventional antioxidants lack these abilities and are therefore likely to be therapeutically less effective [49]. Moreover, H2 has been shown to exhibit anti-inflammatory properties by modulating key transcription factors such as NF-κB, which play a significant role in the chronic inflammation associated with tumorigenesis [50,51]. To elucidate, hydrogen-enriched fluid has been found to inhibit NF-κB, a key transcription factor involved in immune and inflammatory responses [52], and this inhibition may have significant implications for cancer therapy. NF-κB plays a crucial role in cancer development and progression by regulating genes involved in cell proliferation, survival, angiogenesis, and metastasis [53]. Chronic inflammation, often mediated by NF-κB, creates a tumour-promoting environment by enhancing the proliferation of malignant cells and suppressing apoptosis [54].
In cancer cells, NF-κB is frequently constitutively activated, leading to increased expression of anti-apoptotic proteins and cytokines that support tumour growth and resistance to chemotherapy [55]. The inhibition of NF-κB by hydrogen could therefore reduce the inflammatory milieu that support tumour growth and sensitise cancer cells to apoptosis. By suppressing NF-κB activity, hydrogen-enriched treatments such as oxyhydrogen may impair the cancer cells’ ability to resist apoptosis and proliferate, potentially slowing tumour growth [23,24,56] and enhancing the effectiveness of existing therapies [57,58]. Additionally, the reduction in systemic inflammation could improve the overall health and immune function of cancer patients, contributing to better clinical outcomes.
Numerous studies confirm hydrogen’s anti-inflammatory activity, demonstrating reductions in proinflammatory mediators post-administration [3,17]. Moreover, hydrogen has been shown to restore levels of CD8+ cytotoxic T-cells, which destroy dysfunctional cells, thereby improving outcomes in colorectal cancer patients [17]. By dampening the inflammatory response within the tumour microenvironment, oxyhydrogen is shown to inhibit cancer cell proliferation and enhance conventional cancer therapies’ effectiveness. Recent research has also highlighted hydrogen’s pro-apoptotic effects in various cancer cell lines [59], inducing apoptosis by modulating mitogen-activated protein kinase (MAPK) signaling [60]. These findings underscore hydrogen’s multifaceted role in cancer therapy, encompassing antioxidant, anti-inflammatory, and pro-apoptotic mechanisms.

5. Hydrogen Therapies and Lung Cancer

Lung cancer is the leading cause of cancer-related deaths worldwide (12.4% of all cancers globally) and was responsible for almost 2.5 million new cases in 2022 [1]. Preliminary studies suggest that 60% of hydrogen gas may have therapeutic potential in regard to lung cancer treatment [23]. The results showed that oxyhydrogen treatment inhibited cell proliferation, induced apoptosis, and suppressed tumour growth in mouse xenograft models of lung cancer. Additionally, further research demonstrates that oxyhydrogen gas enhanced the sensitivity of lung cancer cells to chemotherapy drugs, suggesting its potential as an adjuvant therapy [61].
In oncological contexts, H2 demonstrates anti-tumour effects by modulating MAPK-associated pathways, which either promote or inhibit apoptosis [19,23,62]. MAPK pathways are of interest, having critical roles in the development and progression of lung cancer through regulation of various cellular processes including cell proliferation, differentiation, survival, and apoptosis, all of which are dysregulated in cancer cells [63]. To illustrate, You et al. (2021) observed increased MAPK protein production in malignant airway epithelial cells (A549 and NCI-H292) after mitogen stimulation, which was reduced by H2 [64]. Further studies by Chu et al. (2019) and Zhu, Cui, and Xu (2021) [65,66] showed that exposing cervical and gastric cancer cell lines (HeLa and MGC-803) to oxyhydrogen gas significantly enhanced apoptosis. These findings suggest that H2 is a crucial regulator of apoptosis, though the precise mechanisms of its action remain to be fully understood.
Recent studies have further elucidated the therapeutic potential of oxyhydrogen, suggesting that H2 modulates MAPK signaling by inhibiting the PI3K/Akt phosphorylation cascade. You et al. (2021) demonstrated that exposing malignant airway epithelial cells (A549 and NCI-H292) to 2% H2 gas for 30 to 60 min significantly reduced MAPK protein production [64]. These findings are corroborated by studies on non-small-cell lung carcinoma (NSCLC) cells, specifically A549 and H1975, where in vitro exposure to high concentrations of H2 gas (60%) markedly decreased malignant cell viability [67].
Similarly, Yang et al. (2020) reported that H2-enriched Dulbecco’s Modified Eagle Medium (DMEM) containing 0.7 mg/L of H2 activated ROS-stimulated pyroptotic pathways, specifically the ROS/Nod-like receptor family pyrin domain containing the 3 (NLRP3)/caspase-1/Gasdermin D pathway, which led to NF-κB-regulated apoptosis [18]. Further investigations into endometrial cancer have also identified the pro-apoptotic effects of H2 gas at varying concentrations (20%, 40%, and 60% H2 with 5% CO2), showing a decrease in the cell surface receptor CD47 and reduced expression of the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein [24].
These studies underscore the multifaceted role of molecular hydrogen in lung cancer therapy, highlighting its potential to influence critical signaling pathways and induce apoptosis in cancer cells. The ongoing research supports the promising application of H2 in oncological treatments, warranting further exploration to fully understand its mechanisms and optimise its clinical use.

6. Hydrogen Therapies and Breast Cancer

Breast cancer is the second most common cancer and, although it can affect both women and men, the global incidence is much higher in women [68]. In 2020, an estimated 2.3 million cases of female breast cancer were diagnosed globally.Approximately 685,000 women died from the disease [69]. However, in high-income countries the prognosis of this condition is generally regarded as favourable, with up to 80% of non-metastatic breast cancers responding to current medical treatments [68]. Nevertheless, treatment of breast cancer can involve a range of medical interventions, including chemotherapeutics, radiotherapy and surgery, that often have incommodious and debilitating consequences for the individual. Frequently reported side effects of treatments include, but are not limited to, chronic fatigue, cognitive and emotional imbalances, nausea and menopausal-type symptoms such as dermal degradation, hair loss, and hot flushes [70].
Breast cancer can be broadly classified into several types based on the presence or absence of certain receptors and other molecular characteristics. For example, invasive ductal carcinoma (IDC), where cancer cells invade the surrounding breast tissue outside the ducts, is a common type of breast cancer [71]. Invasive lobular carcinoma (ILC), however, originates in the glands, or lobules, of the breast and is often associated with metastasis [72]. Factors other than the site of tumorigenesis also have a role in the classification of breast cancer, with epidermal growth factor receptor positive (HER2+) breast cancer being characterised by overexpression of the HER2 protein, known to promote the growth of cancer cells [73]. Contrariwise, triple-negative breast cancer (TNBC) lacks oestrogen, progesterone, and HER2/neu receptors, thus making it more challenging to treat with targeted therapies [74]. Laboratory studies using hydrogen-enriched water have demonstrated the ability of H2 to inhibit breast cancer cell viability by alleviating oxidative distress and inhibiting inflammatory responses. For instance, in vitro models of HER2 mammary tumours in BALB-neuT mice showed that hydrogen-rich water suppressed breast cancer cell survival by targeting vascular endothelial growth factor (VEGF)-induced angiogenesis [22].
From a clinical perspective, a real-world survey involving 82 Stage III and Stage IV cancer patients (including 10 breast cancer patients) explored the effects of inhaled oxyhydrogen gas over a minimum of 3 months. The results indicated substantial improvements in appetite, cognition, fatigue, pain, and sleeplessness after just four weeks of daily inhalation. Notably, 60% of breast cancer patients who received oxyhydrogen therapy reported stabilised physical fitness after three months of treatment [75].

7. Hydrogen Therapies and Colorectal Cancer

Colorectal cancer (CRC), which includes cancers of the colon and rectum, is a common malignancy with significant morbidity and mortality rates and is the third leading cause of cancer-related deaths worldwide [9]. CRC is a major global health problem, with 1.9 million new cases and almost 1 million deaths occurring each year due to the disease [76]. CRC is a malignant neoplasm arising from the colorectal mucosa, typically developing along the adenoma–carcinoma sequence as a result of genetic aberrations in oncogenes, tumour suppressor genes, and mismatch repair (MMR) genes [76]. Studies have shown oxyhydrogen gas to have anti-cancer effects on CRC cells, including HT116, RKO, and SW480 cell lines [24]. In xenograft models of CRC where rodents were exposed to oxyhydrogen for 2 h per day for 21 days, oxyhydrogen was shown to reduce the size and weight of tumours (control tumour size 1500 mm3: oxyhydrogen tumour size 800 mm3) via inhibition of protein kinase B (Akt) phosphorylation, leading to a reduction in stearoyl-CoA 9-desaturase (SCD1) expression and activity [24]. Elevation of SCD1 is positively correlated with cancer progression and poor patient prognosis in numerous malignancies, including breast [77], gastric [78], and lung cancers [79,80]. As SCD1 is an iron (Fe)-containing enzyme, it has been postulated that H2 may affect protein function in either of the following two ways: (1) through direct interactions with the Fe molecule [81,82,83] or (2) by affecting proteins through occupying cavities (pockets) in the protein configuration, supporting form and function [84]. For example, it can be assumed that protecting such redox sensitive moieties as serine 473, the phosphorylation site of protein kinase B, from oxidation would inhibit the downstream effects of PI3K/Akt activation. However, research would benefit from further proteomic and transcriptomic analyses that could help to identify such potential targets of H2 action.
In addition to the direct effects hydrogen has on cell signalling, increasing H2 has been demonstrated to improve intestinal microflora dysbiosis, often cited as a contributing factor to CRC [59,85,86]. In a state of dysbiosis, the gut’s protective microflora decreases while harmful and cancer-promoting microbiota increase. Increased partial pressure of H2 (pH2) is noted to increase short-chain fatty acid (SCFA) production by H2 metabolising microflora whilst concomitantly restricting fermentation by pathogenic Escherichia coli known to promote conditions conducive to cancer, including enhanced angiogenesis, reduced apoptosis, and heightened cell proliferation [87]. The increased production of SCFAs with H2 is intriguing, as SCFAs are integral to gut health (acting as energy substrates for the gut epithelium) and immune cells. SCFAs also have a substantial role as extracellular signalling molecules in gut–brain communications, which may contribute to the improved quality of life reported in patient-reported data [17].
The potential effects of hydrogen-inhalation therapies on malignant cells and tissues is described in Figure 1.

8. Future Perspectives

8.1. Safety

Hydrogen gas is flammable above 527 °C and can explode when mixed with oxygen (. It is recommended that hydrogen should not exceed 4.6% in air or 4.1% by volume in pure oxygen gas [88]. To minimise risks, hydrogen concentrations should not exceed one-third of the lower explosion limit. Reports indicate that hydrogen leakage inside small-scale production devices is a primary cause of explosions [89]. The presence of a transient explosive atmosphere is mainly confined to connective conduits, filter bottles, and a small area around the inhalation tube [90]. Safe hydrogen use requires proper handling and procedures due to its flammability and explosive potential. Pure hydrogen should be stored in appropriate cylinders in well-ventilated areas away from heat sources and direct sunlight [91], posing challenges for clinical use. Regular cylinder checks, proper airflow, ventilation, and the use of detectors and monitors for hydrogen leaks are essential. Training for individuals working with hydrogen should cover safe handling, storage, and emergency procedures, including hazard recognition and incident response.
In a clinical context, the safety of oxyhydrogen-producing devices [89] could likely lead to hesitation in implementing such therapies within a public healthcare setting. However, as O2 is also a hazardous gas, and one that is routinely utilised within healthcare, it is conceivable that oxyhydrogen therapies could be introduced as long as stringent guidelines are adhered to. For instance, when using pure O2 at home, patients are advised not to place canisters close to sources of heat or potential ignition (such as fires, electrical appliances, etc.) [92]. However, oxyhydrogen inhalation therapies use water electrolysis to decompose H2O into H2 and O2, and the gas mixture is consumed upon generation, ceasing to be produced when not in use. This safety feature eliminates the need for hazardous gas storage, as would be required for H2 and O2 individually, potentially enhancing the safety of users and healthcare workers. Oxyhydrogen-generating devices are easy to use, require minimal training and maintenance, and offer a sustainable and ecological method for providing hydrogen inhalation therapies.

8.2. Cost

Another barrier to widespread H2 use in industries, including healthcare, is the high cost of production, primarily due to the energy required for water electrolysis, which accounts for 60–80% of the total cost [93]. However, utilising energy sources such as solar and wind power can reduce these costs. To illustrate, at an electricity rate of USD 0.5 per kWh, hydrogen production via electrolysis is estimated to cost between USD 5 and USD 10 per kg [94]. Scaling up renewable energy sources is expected to cut electrolytic hydrogen production costs by 30–80% by 2050, approaching the current fossil fuel-based hydrogen production costs of USD 1–2 per kg [94]. Therefore, the overall financial viability of using oxyhydrogen in healthcare will need to be assessed by considering the purchase, maintenance, durability, and longevity of oxyhydrogen-generating units compared to conventional methods.

8.3. Research

Although current empirical and clinical research into the effects of hydrogen-containing therapies for various forms of cancer is promising, further research is needed to elucidate the precise mechanisms of action underlying the anti-cancer effects of hydrogen and oxyhydrogen gases. This includes understanding the interactions of such gases with tumour cells, the tumour microenvironment, and the immune system. Advances in molecular and cellular biology techniques, as well as imaging technologies, will facilitate a deeper understanding of such mechanisms and help optimise their therapeutic applications.
To increase the current understanding of H2 biochemistry, it will be necessary to employ several analytical methods on various malignant cell types. For example, Halliwell et al. (1987) developed a simple and cost-effective deoxyribose test tube assay that is able to determine the reaction rate constants of antioxidant compounds with •OH. Here, when •OH-reductive antioxidants are added to the assay, they compete with deoxyribose, a major target for •OH oxidation, and inhibit chromogen formation. The rate constant for the reaction of the antioxidant with hydroxyl radical can then be deduced by analysing the reduction in the colour formation when using spectrophotometric analysis [95]. Utilising such techniques would be useful in providing further information as to whether H2 can directly reduce, or prevent the formation of, this particular radical species.
Another important direction for future research is the development of novel delivery methods for hydrogen and oxyhydrogen gases. While inhalation therapy is currently the most common route of administration, other delivery methods, such as intravenous infusion, topical application, and targeted delivery systems, are being explored [96]. These approaches aim to improve the bioavailability and tissue-specific targeting of hydrogen and oxyhydrogen gases, potentially enhancing their therapeutic efficacy while minimising side effects.
Continued efforts to understand their mechanisms of action, develop innovative delivery methods, and explore combination therapies will pave the way for more effective and personalised cancer treatments. With ongoing research and clinical trials, hydrogen and oxyhydrogen therapies have the potential to revolutionise cancer care and improve the lives of patients worldwide. The integration of hydrogen and oxyhydrogen therapies into multimodal cancer treatment strategies holds promise for improving patient outcomes. Additionally, combination therapies that utilise hydrogen/oxyhydrogen gas alongside conventional chemotherapy, radiotherapy, immunotherapy, or targeted therapies [9,10,96,97,98] may also offer synergistic benefits and may lead to better response rates and prolonged survival for cancer patients. However, the long-term effects of hydrogen inhalation therapies in cancer patients have yet to be extensively investigated and further clinical inquiry is warranted.

9. Summary and Conclusions

In summary, oxyhydrogen gas shows promising potential as a therapeutic agent for the treatment of various types of cancer, including breast, lung, and colorectal cancer. Research studies have demonstrated its anti-cancer effects in empirical and preclinical settings, highlighting its ability to inhibit tumour growth, induce apoptosis, and enhance the efficacy of conventional cancer therapies. Through enhancing regulatory activities on redox chemistry and modulating both adaptive and innate immune responses, H2 therapeutics have been shown to protect and restore homeostatic cellular function in both in vitro [11,21,22,23,24] and in vivo [12,13,14,15] research. As molecular hydrogen and oxygen are both well tolerated and non-toxic in analeptic doses, excesses do not accumulate in the body and are facilely eliminated in the breath. This reduces the risk of adverse reactions to treatment, and, to-date, no unresolvable side-effects of oxyhydrogen therapies have been recorded.
In conclusion, the integration of oxyhydrogen gas into cancer treatment regimens represents a promising avenue for enhancing therapeutic outcomes. Ongoing research is essential to fully elucidate the molecular mechanisms underlying its effects and to optimise its application in clinical settings. A growing body of evidence supports the potential of oxyhydrogen gas as a valuable adjunct in the fight against cancer, warranting further investigation and development.

Author Contributions

Conceptualisation, G.R. and A.N.; writing—original draft preparation, G.R.; writing—review and editing, A.N. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Water Fuel Engineering, Wakefield, U.K. Company number: 08466023.

Conflicts of Interest

The authors declare that this study received funding from Water Fuel Engineering who have a commercial interest in alkaline water electrolysis devices. The funder had the following involvement with the study: Conceptualization. A. Nenov is a board member of Water Fuel Engineering. Grace Russell is subcontracted to Water Fuel Engineering as an R&D consultant.

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Oxygen 04 00020 g001
Figure 1. The potential effects of hydrogen therapies in lung, breast and colorectal cancers. Upwards arrows indicate increases. Downward arrows indicate decreases. NF-ᴋB: nuclear factor kappa-light-chain-enhancer of activated B cells. PI3K/Akt: phosphatidylinositol 3-kinase/protein kinase B. MAPK: mitogen-activated protein kinase. SCD1: stearoyl-CoA 9-desaturase. VEGF: vascular endothelial growth factor. SCFA: short-chain fatty acid.
Figure 1. The potential effects of hydrogen therapies in lung, breast and colorectal cancers. Upwards arrows indicate increases. Downward arrows indicate decreases. NF-ᴋB: nuclear factor kappa-light-chain-enhancer of activated B cells. PI3K/Akt: phosphatidylinositol 3-kinase/protein kinase B. MAPK: mitogen-activated protein kinase. SCD1: stearoyl-CoA 9-desaturase. VEGF: vascular endothelial growth factor. SCFA: short-chain fatty acid.
Oxygen 04 00020 g001
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Russell, G.; Nenov, A. Oxyhydrogen Gas: A Promising Therapeutic Approach for Lung, Breast and Colorectal Cancer. Oxygen 2024, 4, 338-350. https://doi.org/10.3390/oxygen4030020

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Russell G, Nenov A. Oxyhydrogen Gas: A Promising Therapeutic Approach for Lung, Breast and Colorectal Cancer. Oxygen. 2024; 4(3):338-350. https://doi.org/10.3390/oxygen4030020

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Russell, Grace, and Alexander Nenov. 2024. "Oxyhydrogen Gas: A Promising Therapeutic Approach for Lung, Breast and Colorectal Cancer" Oxygen 4, no. 3: 338-350. https://doi.org/10.3390/oxygen4030020

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