Hydrogen Inhalation Therapy And Its Role In Cancer

1. Molecular Hydrogen Basics

Molecular hydrogen is a small, colorless, tasteless, and odorless non-toxic gas with poor water solubility (1, 2). It is constituted in deep sea diver’s gas cylinders to help them breathe and avoid nitrogen sickness and decompression (3). An extensive research has been carried out past few decades on the benefits of hydrogen applications in a clinical setting featuring its anti-inflammatory, anti-oxidative, and anti-cancer properties (3, 4). Firstly, Dole et al explored the therapeutic potential of hydrogen gas in cancer. They reported that 2 weeks of hyperbaric hydrogen treatment caused significant repression of skin tumors in mice models (5). However, concerns regarding storage, transportation, and administration of hyperbaric hydrogen limited the use of this therapy. Nonetheless, a study conducted by Ohsawa et al in 2007 advocated that inhalation of small amounts of hydrogen gas could exert a neuroprotective effect by reducing oxygen radicals levels in ischemia-reperfusion or inflammation animal models (6). Since then, the promising therapeutic effects of molecular hydrogen have grasped an increasing attention. Several studies have examined the positive effects of hydrogen against inflammation, injury, metabolic syndromes, and cancer (7).        

2. Hydrogen Role In Managing Treatment (Chemo And Radio) Side Effects

Cancer is a heterogeneous and complex disease. It is a global health concern and the second major cause of mortalities in the world. Cancer management has been a complex process. Surgery, chemotherapy, and radiotherapy are the most widely opted treatment approaches for cancer (8). These treatment methods are linked with many adverse effects such as chemotherapy and radiotherapy cause oral mucositis, hepatotoxicity, hematopoietic system injury, gastrointestinal toxicity, nephrotoxicity, neurotoxicity, and cardiotoxicity in cancer patients. Nevertheless, these harmful impacts impede the clinical interventions of these conventional therapies in cancer management (9, 10). Additionally, they negatively affect the quality of life of a cancer patient and thus may lead to therapy discontinuation (11). Therefore, it is imperative to devise effective management approaches against radiotherapy and chemotherapy-stimulated side effects.

Growing evidence has indicated that the molecular hydrogen gas can help relieve the adverse effects of conventional chemotherapy treatment. Moreover, it can also reduce the cancer cell growth and xenograft tumor, suggesting its prospective applications in clinical treatment (12, 13). Studies have shown that molecular hydrogen therapy can be combined with conventional cancer treatments i.e., surgical resection, radiotherapy, and chemotherapy, which often cause systemic inflammation, to reinstate normal tissue functioning (14). 

Another study used hydrogen inhalation therapy in the radiation-stimulated dermatitis and skin injury mice model. The results indicated that the pre-inhalation of hydrogen gas can significantly decrease the severity of radiation-induced dermatitis conditions and also accelerate the wound healing process (15).

A study evaluated the clinical safety and efficacy of hydrogen inhalation in patients with hearing impairment after chemotherapy/radiotherapy for nasopharyngeal cancer. The investigations revealed that hydrogen inhalation improved hearing in patients suggesting it as alternative rehabilitation therapy. Moreover, no other side effects such as vomiting, dizziness, nausea, chest pain, nosebleed, earache, and allergic reaction were observed after hydrogen inhalation (16). These studies infer hydrogen inhalation as a potent management strategy for combating radiotherapy and chemotherapy side effects and improving the quality of life in cancer patients.

Considering this evidence, hydrogen inhalation therapy is currently being administered as an effective treatment approach against cancer. Moreover, it is also reported to be used as an adjuvant with chemotherapy and radiotherapy to combat their side effects and increase treatment effectiveness.                                                                                                                              

3. Hydrogen Inhalation Role In Cancer Management

Anti-cancer drugs are the most common therapeutic methods used for cancer treatment. However, many drugs have resulted in unsatisfactory therapeutic effects. Concerning this issue, hydrogen gas has not been reported to have any side effects like conventional anti-cancer drugs. Moreover, the hydrogen therapy is stated useful against many diseases triggered by chronic inflammation and oxidative stress (17). An effective anticancer treatment is laced with a proactive approach to killing cancer via deteriorating all its favorable surviving mechanisms. Here some basic mechanisms concerning hydrogen inhalation-mediated cancer management are discussed:

a. Removal of Reactive Oxygen Species (ROS)

Cancer is largely caused by mutations in nuclear and mitochondrial DNA. The mutations arise due to potent oxidizing reactive oxygen species (ROS) (17). ROS production increases in tumor cells as a result of gene mutation, upsurge in metabolic rate, and relative hypoxia. These reactive oxygen species are quenched by increased antioxidant enzymatic and non-enzymatic pathways of the cell. A moderate upsurge in ROS is responsible for many pathologic conditions such as tumor promotion and development. Furthermore, they are involved in the regulation of different cell signaling cascades. Additionally, ROS can initiate programmed cell death (18). 

Molecular hydrogen possesses antioxidant properties. Studies showed that hydrogen gas inhalation could correct oxidative /antioxidative imbalance and exert an anti-tumor effect. Hydrogen selectively decreases oxidants of the harmful reactive oxygen species encompassing -OH (hydroxyl radicals) and ONOO- (peroxynitrite radicals) which cause tumor progression, cell invasion, metastasis, and cell proliferation. However, H2 does not interrupt metabolic oxidation-reduction reactions involved in cell signaling (19). Consequently, it is an effective antioxidant that can prevent cancer progression and development.

b. Controls Inflammation

Inflammatory cytokines are dysregulated in many diseases including cancer. They are a sequence of signal molecules that facilitate innate immune responses (20-22). They comprise tumor necrosis factors (TNFs) excreted by macrophages and interleukins (ILs) produced by white blood cells. Both of these are strongly involved in cancer onset and progression (12). Studies have shown that hydrogen gas can suppress both interleukins and tumor necrosis factors and help control inflammation (23, 24). 

Furthermore, chemotherapeutic treatment in cancer patients induces inflammation that not only exerts severe harmful effects (25, 26) but also results in cancer metastasis and treatment failure (27, 28). Therefore, by controlling inflammation, hydrogen gas could inhibit tumor formation, and development and represses the chemotherapy/radiotherapy-mediated adverse effects (29). Thus, it can help maintain treatment effectiveness and improve patient life quality.

c. Improved Mitochondrial Function

Mitochondria play a critical role in the health and pathogenesis of many diseases as it is the hub of oxidative metabolism and the main site of reactive oxygen species production (30). It approximately produces 90% of reactive oxygen species (ROS). The inequity between the mitochondrial production of reactive oxygen species and their removal from the cell due to an increase in ROS production and decline in antioxidant molecules leads to oxidative stress. This causes oxidative damage to cell constituents including DNA, proteins, and lipids (31). Studies have shown that molecular hydrogen pretreatment protects cells from hydrogen peroxide (H2O2) mediated cell death and improves mitochondrial function. This is accompanied by an upsurge of oxidative stress levels followed by induced expression of anti-oxidative enzymes (32). Hydrogen mainly scavenges OH or hydroxyl radicals which is the most potent oxidant among ROS (33). Interestingly, molecular hydrogen is able to cross the blood-brain barrier. Thus, utilizing its exceptional diffusivity, hydrogen easily passes biological membranes to reach mitochondria and helps cells by providing protection against cell damage inferred by hydroxyl radical (OH) (34, 35). This not only improves mitochondrial dysfunction and eliminates ROS but also treats cancer proactively.

d. Improves Immune Function

As cancer is an inflammatory illness and immune cells involved in human malignancy or cancer development may alter and comprise both innate and adaptive immune system cells. Innate immune cells are macrophages and neutrophils whereas adaptive immune reaction components include T and B lymphocytes (36). Hydrogen gas possesses a potent therapeutic potential to improve immune system functions deregulated via cancer. Research has indicated that hydrogen gas may repress tumors by stimulating cancer immunity or via upsurging the survival of tumor-invaded tissues (37). A study examined the effect of hydrogen gas on CD8+ T cells that play a critical role in cancer growth and metastasis. Moreover, these T cells are imperative for exerting anti-tumor effects. The study showed that the hydrogen gas particularly reduces the amount of depleted or exhausted CD8+ T cells and increases the active CD8+ T cells, thus improving overall survival and progression-free survival, (38). 

4. Genes/Signaling Pathways Impacted By Hydrogen Inhalation

As we know cancer is a complex and multifactorial disease. It can be genetic and sporadic. In both cases, genes are involved that go awry due to any stimulus either exogenous including environmental factors, or endogenous involving anything that arises at the cell or molecular level in the body.Since the discovery of cancer-causing genes i.e., RAS, KIT, MYC, and BRAF, and tumor suppressor genes i.e., TP53, PTEN, and BRCA1, cancer-associated genetic abrasions have been widely recorded. Currently, complex signaling cascades and molecular networks are known for their crucial roles in cancer onset and also in potential treatment therapies or treatments. Moreover, they help in executing and regulating important cell survival and growth processes (39). Program cell death or apoptosis is also regulated by the expression of apoptosis-related enzymes such as B-cell lymphoma-2-associated X protein (Bax), anti-apoptotic B-cell lymphoma-2 (Bcl-2), and caspases-3, 8, and 12. Hydrogen gas at certain concentrations was found to repress pro-apoptotic Bax gene and caspase 3,8,12 expression and increase anti-apoptotic Bcl-2 gene expression (40).

 pAKT/SCD1 pathway is an important signaling pathway involved in the regulation of colorectal cancer cell proliferation. Here, SCD1 or stearoyl-CoA desaturase is an enzyme involved in fatty acid biosynthesis. Whereas Akt is a serine/threonine kinase which is involved in the regulation of multiple cellular processes. A recent study showed that a high concentration of molecular hydrogen suppressed the pAKT/SCD1 pathway to inhibit colorectal cancer cell proliferation and thus cancer progression (41). 

In addition to this, hydrogen treatment improves UVB radiation-stimulated oxidative stress by preventing the Nrf2/HO‑1 gene activation via PI3K/Akt pathway regulation. This UVB-induced oxidative stress exerts detrimental effects on the skin and causes skin damage (42). 

Similarly, molecular hydrogen is reported to enhance program cell death (apoptosis) and autophagy by suppressing the activation of the STAT3/Bcl2 signaling cascade in lung cancer cells. Moreover, autophagy suppression increases molecular hydrogen’s role in encouraging cancer cell apoptosis (43). 

Besides, molecular hydrogen is reported to regulate autophagy by increasing HO-1 and reducing the expression of MAPK and NF-κB signaling, suggesting, close crosstalk between inflammation, autopay, and reactive oxygen species (44). 

All these studies showed that complexity in cancer disease progression and development can only be encountered with a proactive and specifically designed targeted approach.

5. Some Human Trial Case Examples    

Considering the antioxidant and anti-inflammatory properties of molecular hydrogen, it has been studied in many preclinical and clinical trials on several diseases linked with inflammatory and oxidative stresses (45). However, the number of clinical studies is limited related to cancer disease.

In a clinical study conducted in 2016, hydrogen gas inhalation was indicated safe in patients with post-cardiac arrest syndrome, thus suggesting the application of its appealing therapeutic effects in other diseases (46). 

A follow-up study was conducted on 82 advanced-stage cancer patients mainly of stage III and IV. The patients were treated with hydrogen inhalation. After 3-46 months, 12 patients with stage IV died. After 4 weeks of hydrogen inhalation, significant improvement was observed in insomnia, fatigue, anorexia, and pain. Further, 41.5% of patients showed improvement in physical well-being. In 58 patients, one or more aberrant tumor markers were improved. The best results were observed in lung cancer patients compared to pancreatic and liver carcinomas. Moreover, the disease control rate was reported to be greater in stage III cancer patients. Additionally, no side effects of hydrogen inhalation therapy were observed except in one individual with minor adverse effects resolved immediately (47).

Another small clinical study explored the effect of hydrogen inhalation in cancer patients administered with intensity-modulated radiation therapy. The results showed that hydrogen improved the harmful effects of radiation therapy on bone marrow without conceding the anti-cancer effects of therapy. However, the study had some limitations concerning the number of involved patients, data collection, and observational analysis from a single hospital (48). 

All these profound studies indicate that hydrogen inhalation therapy could be an effective, safe, and low-cost treatment for cancer. However further studies are required to design the effective concentration and time for administration of molecular hydrogen for a wide range of cancers. 

                                                                       

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