Hydrogen: an advanced and safest gas option for cancer treatment

Currently available cancer treatment options, such as surgery, chemotherapy, radiation, and immunotherapy, are limited, and the results could be unsatisfactory due to systemic toxicity and drug resistance. Recently, gas therapies have received widespread attention for cancer treatment. Various gaseous molecules, such as nitric oxide (NO), carbon monoxide (CO), oxygen, hydrogen, hydrogen sulfide (H2S), and sulfur dioxide, have been studied for their anticancer properties (Additional Table 1).Additional Table 1: Potential anticancer properties of different gaseous moleculesHowever, the reliability and implications of anticancer gas therapy are not fully understood. Precise and safe methods for gas therapy are being explored to overcome operational problems such as difficult handling, strenuous delivery systems, low solubility in water, high tissue penetration, random diffusion in the body, low accumulation in target tissues, and poisoning. In addition, the anticancer mechanism of most gases, including NO, H2S, and CO, is concentration dependent; only gases with high concentrations (≥ nM) are toxic to cancer cells, while low concentrations (< nM) of these gases may reverse the anticancer properties and protect cancer cells.1,2 Overall, many of these methods are either limited or toxic, especially in advanced cancer cases or metastatic cases.3 The toxicity of most of these gases is due to their high binding affinity for hemoglobin, which poses a serious risk for their implementation, especially for inhalation. Comparatively, molecular hydrogen (H2) is a nontoxic gas and does not induce hemoglobin- related toxicity as CO2, NO or H2S do. High levels of H2 antioxidants and their broad range of therapeutic potential have been studied in several cancer models, including lung, gallbladder, liver, and brain metastasis models.4 H2 has remarkable antioxidant and neuroprotective effects and other advantages, such as swift penetration ability to cross the blood–brain barrier, biomembranes, and diffusion into the cytosol and organelles without harming healthy cells.5 In addition, H2 can be used in various forms according to target diseases, such as in the form of hydrogen water, hydrogen saline, and hydrogen nanocrystals. However, the inhalation of hydrogen gas and the oral ingestion of hydrogen-rich saline are the two most common systemic routes of hydrogen administration. H2 inhalation therapy has also been proposed in several countries as the safest mode of H2 administration.6,7 H2 inhalation may be an easy and safe approach for cancer treatment. Recent results from cancer cell lines and animal models indicate that H2 can affect abnormal cell division by modulating several regulatory factors and tumor markers (Figure 1).6 A HeLa xenograft mouse model showed that H2 inhalation may increase the apoptosis rate, proliferation, and oxidative stress in HeLa cells. H2 may affect tumor growth by regulating the expression of overexpressed subunits of transcription factors, such as hypoxia-inducible factor 1α and the nuclear factor-κΒ p65 subunit.8Figure 1: H2 Inhalation effects on tumorous and normal cells.CD47: Cluster of differentiation 47; CDC42: cell division control protein 42; H2: molecular hydrogen; ROS: reactive oxygen species.H2 inhibits cell division control protein 42 and cluster of differentiation (CD) 47 in lung cancer cells; this regulates abnormal proliferation and increases the susceptibility of tumorous cells to immune attack by macrophages and dendritic cells. Similarly, H2 promotes the expression of proinflammatory factors such as tumor necrosis factor α and interleukin 6.9-11 Hydrogen also increases the expression level of p53 tumor suppressor proteins. The p53 protein disrupts the membrane potential of mitochondria, induces autophagy, and suppresses reactive oxygen species in cancer cells.12 A clinical study from Tamana Regional Health Medical Center in Japan highlighted the concept of H2 inhalation for improving cancer treatment. This study revealed that hydrogen gas inhalation 3 h/d can improve the prognosis and overall survival of stage IV colorectal carcinoma patients by decreasing the number of programmed cell death 1/CD8+ T cells. Factors such as exhausted terminal programmed cell death 1/CD8+ T cells in the peripheral blood are linked with worse progression-free survival and overall survival. Exhausted CD8+ T cells usually lose their immunological potential due to mitochondrial dysfunction caused by inactivation of peroxisome proliferator-activated receptor γ coactivator 1α, which results in a poor prognosis in cancer patients.13 Despite the emerging advantages of gas signaling molecules such as H2 in tumor cell growth regulation, clinical implementation and outcomes are lacking. Several uncertainties are still associated with H2 administration. However, a study revealed that H2 reversed the effects that induce cell proliferation in human cancer lines.14 Other challenges with H2 anticancer therapy may encountered due to its limitedly understood mechanism, systemic administration, poor targeting, and utilization hazards, such as its explosive nature.4 Comparatively, many studies have shown that hydrogen inhalation is the safest and most efficient way to treat cancerous cells, at least for respiratory cancers. Another tumor site can be better targeted with nanocarrier-mediated H2 delivery.15 We suggest that anticancer H2 therapy is a safe, adjuvant or supportive therapeutic solution to increase the quality and results of conventional cancer treatment because of its inherent biosafety and remarkable therapeutic potential. H2 anticancer therapy can minimize the debilitating side effects of conventional anticancer therapies by improving survival, quality of life, and blood parameters. Handling and utilization-related issues can be resolved with technical advancements and safety precautions. However, as an independent cancer treatment option, significant clinical work is suggested in this direction. NG works in River Engineering Private Limited as the R & D officer, and all the authors do not have any conflicts of interest.