Hydrogen Gas in Cancer TreatmentScientific Research

Published on: 20190608

Hydrogen Gas in Cancer Treatment

 Doi:  10.3389/fonc.2019.00696

Sai Li , ^1, † Rongrong Liao , ^2, † Xiaoyan Sheng , ^2, † Xiaojun Luo , ³ Xin Zhang , ¹ Xiaomin Wen , ³ Jin Zhou , ^2, * and Kang Peng ^1, 3, *

Gas signaling molecules (GSMs), composed of oxygen, carbon monoxide, nitric oxide, hydrogen sulfide, etc., play a crucial role in regulating signaling and cellular homeostasis. Interestingly, through various routes of administration, these molecules also showed potential to treat cancer. Recently, hydrogen gas (molecular formula: H2) has emerged as another GSM with various biological activities, including anti-inflammatory, anti-ROS and anti-cancer effects. Growing evidence suggests that hydrogen can both alleviate side effects caused by traditional chemotherapeutic drugs and inhibit the growth of cancer cells and xenograft tumors, suggesting its broad and effective use in clinical therapy. In the current review, we summarize these studies and discuss potential mechanisms. The application of hydrogen in cancer therapy is still in its infancy and requires further mechanistic studies and the development of portable instruments.

Introduction

Gas Signal Molecules (GSMs) refer to a group of gas molecules such as oxygen (1), nitric oxide (2), carbon monoxide (3), hydrogen sulfide (4), sulfur dioxide (5, 6), ethylene (7). , 8) etc. These gaseous molecules have several key functions in regulating cell biology in vivo through signal transduction (9). More importantly, when used directly or in certain pharmaceutical formulations, certain GSMs are useful as therapeutics for primary cancers as well as for multidrug-resistant cancers (9-13). In addition, some of these GSMs can be produced in the body by various bacteria or enzymes (eg, nitric oxide, hydrogen sulfide), suggesting that they are more compatible molecules that may have fewer side effects than traditional chemotherapy drugs (9, 14). , 15) . . Hydrogen has recently been recognized as another important GSM in biology, with tantalizing potential in healthcare due to its role in preventing cellular damage from various attacks

For the molecular formula H2, hydrogen is the lightest molecule in nature, making up only about 0.5 parts per million (ppm) of all gases. Hydrogen is essentially a colorless, odorless, tasteless, non-toxic, highly flammable gas that can form explosive mixtures with air at concentrations ranging from 4% to 74% and can be triggered by sparks, heat, or sunlight. Hydrogenases of certain members of the human gastrointestinal microbiota can generate small amounts of hydrogen gas from unabsorbed carbohydrates in the gut through catabolism and metabolism (20, 21), which are then partially diffused into the bloodstream and released and detected in vivo in exhalation of respiration (20), indicating its potential as a biomarker.

As the lightest molecule in nature, hydrogen exhibits attractive permeation properties as it can diffuse rapidly across cell membranes. Animal model studies have shown that after oral administration of ultra-hydrogen-rich water and ultra-hydrogen-rich saline intraperitoneally, the hydrogen concentration peaks at 5 minutes; while intravenous injection of HSRS takes 1 minute. Another in vivo study tested the distribution of hydrogen in the brain, liver, kidney, mesenteric fat, and thigh muscles of rats after inhalation of 3% hydrogen. The order of hydrogen concentration at saturation was liver, brain, mesentery, muscle, kidney, indicating that the distribution between organs in rats was different. With the exception of thigh muscles which take longer to reach saturation, other organs take 5-10 minutes to reach maximum hydrogen concentration. Meanwhile, the liver has the highest Cmax. This information may guide future clinical applications of hydrogen.

Although hydrogen gas was studied as early as 1975 as a treatment for mouse models of cutaneous squamous cell carcinoma, its potential for medical applications was not fully explored until 2007 by Oshawa et al. Hydrogen has attracted worldwide attention by being reported to ameliorate cerebral ischemia-reperfusion injury by selectively reducing cytotoxic reactive oxygen species including hydroxyl radicals and peroxynitrite. Through various formulations, hydrogen has been used as a drug for the treatment of Parkinson’s disease, rheumatoid arthritis, brain injury, ischemia-reperfusion injury, diabetes and other diseases.

What’s more, hydrogen has been shown to improve clinical endpoints and surrogate markers, from metabolic diseases to chronic systemic inflammatory diseases and cancer.A 2016 clinical study showed that hydrogen inhalation is safe for patients with post-cardiac arrest syndrome, and its further therapeutic use in other conditions becomes more attractive.

In the current overview, we focus on applications in cancer therapy. Generally, hydrogen can exert its biological functions by regulating ROS, inflammatory and apoptotic events.

Hydrogen Gas Selectively Scavenges Hydroxyl Radical and Peroxynitrite, and Regulates Certain Antioxidant Enzymes

To date, many studies have shown that hydrogen does not target specific proteins, but instead regulates several key players in cancer, including ROS and certain antioxidant enzymes (36).

ROS refers to a series of unstable oxygen-containing molecules, including singlet oxygen, hydrogen peroxide, hydroxyl radicals, superoxide, nitric oxide, and peroxynitrite. Once generated in vivo, ROS can damage proteins, DNA/RNA, and lipids in cells due to their high reactivity, causing severe damage, leading to apoptosis. The presence of ROS can induce cellular stress and damage through a mechanism called oxidative stress, leading to cell death. Normally, under bodily conditions, cells, including cancer cells, maintain a balance between the formation and elimination of ROS, which is critical for their survival. Excessive production of ROS, resulting from an imbalance of regulatory systems or external chemical attack, can trigger an internal cascade of apoptosis and cause severe toxic effects.

Hydrogen can act as a ROS regulator. First, as demonstrated by Ohsawa et al. Hydrogen was demonstrated to selectively scavenge the most cytotoxic ROS, •OH, as tested in a rat model of acute cerebral ischemia and reperfusion (26). Another study also confirmed that hydrogen can reduce oxygen toxicity induced by hyperbaric oxygen by effectively reducing •OH (46).

Second, hydrogen can induce the expression of some antioxidant enzymes that can eliminate ROS and play a key role in regulating redox homeostasis in cancer cells (42, 47). Studies have shown that hydrogen treatment increases the expression of superoxide dismutase (SOD) (48), heme oxygenase 1 (HO-1) (49), and nuclear factor erythroid 2-related factor 2 (Nrf2) (50). , significantly increased and enhanced its ROS-eliminating potential.

By modulating ROS, hydrogen can be used as an adjunctive regimen to reduce side effects in cancer therapy without reversing the cytotoxicity of other therapies such as radiotherapy and chemotherapy (48, 51). Interestingly, the administration of hydrogen can initially reduce ROS levels due to the excess production of ROS in cancer cells (38), but due to a compensatory effect, it triggers more ROS production, leading to cancer cell killing.

Hydrogen Gas Suppresses Inflammatory Cytokines

Inflammatory cytokines are a group of signaling molecules that mediate innate immune responses, and their dysregulation may lead to many diseases, including cancer (53-55). Typical inflammatory cytokines include interleukins (ILs) secreted by leukocytes, tumor necrosis factors (TNFs) secreted by macrophages, both of which have been shown to be closely associated with cancer initiation and progression (56-59), and Both ILs and TNFs can be inhibited by hydrogen gas (60, 61).

Inflammation induced by chemotherapy in cancer patients not only causes severe side effects (62, 63), but also leads to cancer metastasis and treatment failure (64, 65). By modulating inflammation, hydrogen can prevent tumor formation and progression, as well as reduce side effects from chemotherapy/radiotherapy (66).

Hydrogen Gas Inhibits/Induces Apoptosis

Apoptosis, also known as programmed cell death, can be triggered by extrinsic or intrinsic signals and proceeds through various molecular pathways, serving as an effective cancer treatment strategy (67, 68). In general, apoptosis can be induced by (1) activation of cell surface death receptors (such as Fas, TNF receptors, or TNF-related apoptosis-inducing ligands), (2) survival signals (such as epidermal growth factor receptor, pro- Mitogen-activated protein kinase or phosphoinositide 3-kinase) and (3) activation of pro-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins or down-regulation of anti-apoptotic proteins (such as X-linked inhibitor of apoptosis protein , survival and der apoptosis inhibitors) (69, 70).

Hydrogen can regulate intracellular apoptosis by affecting the expression of apoptosis-related enzymes. At a certain concentration, it can both act as an inhibitor of apoptosis by inhibiting pro-apoptotic B-cell lymphoma-2-associated X protein (Bax), caspase-3, 8, 12 and anti-apoptotic B-cell-enhancing lymphoma. Action-2 (Bcl-2) (71) or by contrasting mechanisms as an inducer of apoptosis (72), suggesting its potential to protect normal cells from anticancer drugs or inhibit cancer cells.

Hydrogen Gas Exhibits Potential in Cancer Treatment

Hydrogen Gas Relieves the Adverse Effects Related to Chemotherapy/Radiotherapy

Chemotherapy and radiotherapy remain the main strategies for treating cancer (73, 74). However, cancer patients receiving these treatments often experience fatigue and reduced quality of life (75-77). The spike in ROS formation during treatment is thought to cause side effects, leading to significant oxidative stress and inflammation (41, 42, 78). Therefore, hydrogen gas benefits from its antioxidant, anti-inflammatory and other cytoprotective properties and can be used as an adjunctive treatment regimen to suppress these side effects.

Patients with non-small cell lung cancer frequently develop severe acute interstitial pneumonia when treated with gefitinib, an epidermal growth factor receptor inhibitor (79). In a mouse model of oral gefitinib and intraperitoneal injection of naphthalene, hydrogen-rich water treatment resulted in a significant reduction of inflammatory cytokines such as IL-6 and TNFα due to severe lung injury due to oxidative stress. Bronchoalveolar lavage fluid relieves pneumonia. More importantly, hydrogen-rich water did not affect the overall antitumor effect of gefitinib in vitro and in vivo, on the contrary, it counteracted the weight loss induced by gefitinib and naphthalene and improved overall survival, suggesting that hydrogen As a promising adjuvant, it has the potential to be used in clinical practice to improve the quality of life of cancer patients (80).

Doxorubicin, an anthracycline antibiotic, is a potent anticancer agent for various cancers, but its use is limited to fatal dilated cardiomyopathy and hepatotoxicity (81, 82). An in vivo study showed that intraperitoneal injection of hydrogen-rich saline improved doxorubicin-induced mortality and cardiac insufficiency. This treatment also attenuated histopathological changes in rat serum such as B. brain natriuretic peptide (BNP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin and malondialdehyde (MDA) levels in serum.Mechanistically, hydrogen-rich saline significantly reduced ROS levels and inflammatory cytokines TNF-α, IL-1β, and IL-6 in cardiac and liver tissues. Hydrogen-rich saline also induced a decrease in the expression of apoptotic Bax, cleaved caspase-3, and higher anti-apoptotic Bcl-2, resulting in decreased apoptosis in both tissues (71). The present study suggests that hydrogen-rich saline treatment may enhance its protective effect by inhibiting the inflammatory TNF-α/IL-6 signaling pathway, increasing cleaved C8 expression and Bcl-2/Bax ratio, and attenuating apoptosis. Heart and liver tissue (71).

Hydrogen-rich water also showed renoprotective effects against cisplatin-induced nephrotoxicity in rats. In the study, blood oxygen content-dependent (BOLD) magnetic resonance imaging (MRI) images obtained in the different treatment groups showed creatinine and blood urea nitrogen (BUN) levels, two parameters associated with nephrotoxicity were significantly higher in the cisplatin-treated group to those in the control group. Treatment with hydrogen-rich water significantly reversed the toxic effects and showed higher transverse relaxation rates by eliminating oxygen radicals (83, 84).

Another study showed that both inhaling hydrogen (1% hydrogen in air) and drinking hydrogen-rich water (0.8 mM hydrogen in water) reversed cisplatin-induced mortality and weight loss due to its antioxidant properties . Both treatments improved metamorphosis, while reducing renal apoptosis and nephrotoxicity, as assessed by serum creatinine and BUN levels. More importantly, hydrogen did not affect the antitumor activity of cisplatin against cancer cell lines in vitro and in tumor-bearing mice (85). Similar results were found by Meng et al. observed because they showed that hydrogen-rich saline inhibited the release of follicle-stimulating hormone, increased estrogen levels, improved follicular development and reduced cisplatin-induced damage to the ovarian cortex. In this study, treatment with cisplatin resulted in higher levels of oxidative products and inhibition of antioxidant enzyme activity.Hydrogen-rich saline can reverse these toxic effects by reducing MDA and restoring the activity of two important antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT). Furthermore, hydrogen-rich saline stimulates the Nrf2 pathway in ovarian-damaged rats (86).

The mFOLFOX6 regimen, consisting of folinic acid, 5-fluorouracil, and oxaliplatin, is used as first-line treatment for metastatic colorectal cancer, but it also has toxic effects on the liver, resulting in poor quality of life in patients (87, 88). . in China A clinical study was conducted to investigate the protective effect of hydrogen-rich water on liver function in colorectal cancer patients treated with mFOLFOX6 chemotherapy (144 patients, 136 of whom were included in the final analysis). The results showed that the placebo group had mFOLFOX6 chemotherapy-induced adverse reactions, as measured by increased levels of ALT, AST, and indirect bilirubin (IBIL), while the hydrogen-rich water combination group had no difference in liver function during treatment, possibly due to it. antioxidant activity, suggesting that it is a promising protective agent for ameliorating mFOLFOX6-induced liver injury

Most of the adverse effects of ionizing radiation on normal cells are caused by hydroxyl radicals. Combining radiation therapy with some forms of hydrogen may help alleviate these side effects (89). In fact, several studies have found that hydrogen can protect cells and mice from radiation (48, 90).

Tested in a rat skin injury model using a 44 Gy electron beam, the hydrogen-rich water-treated group had a higher proportion of SOD activity and less MDA and IL-6 in the injured tissue compared to the control group and distilled water. water group. In addition, hydrogen-rich water shortens the healing time and improves the healing rate of skin lesions (48).

Gastrointestinal toxicity is a common side effect induced by radiotherapy, which impairs the life quality of cancer patients (91). As shown in Xiao et al.’s study in mice model, hydrogen-water administration via oral gavage increased the survival rate and body weight of mice which were exposed to total abdominal irradiation, accompanied with an improvement in gastrointestinal tract function and the epithelial integrity of the small intestine. Further microarray analysis revealed that hydrogen-water treatment up-regulated miR-1968-5p, which then up-regulated its target myeloid differentiation primary response gene 88 (MyD88, a mediator in immunopathology, and gut microbiota dynamics of certain intestinal diseases involving toll-like receptors 9) expression in the small intestine after total abdominal irradiation (92).

Gastrointestinal toxicity is a common side effect of radiation therapy and affects the quality of life of cancer patients (91). As reported in the study by Xiao et al. It was demonstrated in a mouse model that administration of hydrogen water by oral gavage increased survival and body weight in mice exposed to whole abdominal irradiation, accompanied by improvements in gastrointestinal function and intestinal epithelial integrity. Further microarray analysis revealed that hydrogen water treatment up-regulated miR-1968-5p and then mutated its primary myeloid differentiation response gene 88 (MyD88, a mediator of immunopathology, and gut microbiota dynamics in certain intestinal diseases). Charges and recipients 9) in the small intestine after whole abdominal irradiation (92).

Hydrogen Gas Acts Synergistically With Thermal Therapy

A recent study found that hydrogen can enhance the effects of photothermal therapy. Zhao et al. Hydrated Pd nanocrystals (named PdH0.2) were designed as multifunctional hydrogen carriers for tumor-directed delivery (due to 30 nm cubic Pd nanocrystals) and controlled release of bioreductive hydrogen (due to lattice-bound hydrogen). PD). As shown in this study, hydrogen evolution can be modulated by the power and duration of near-infrared (NIR) irradiation. Treatment with PdH0.2 nanocrystals plus NIR irradiation resulted in higher initial ROS loss in cancer cells, and the subsequent ROS rebound was also much higher than in normal cells, resulting in more apoptosis and severe inhibition of mitochondrial metabolism in cancer cells, but abnormal cells. The combination of PdH0.2 nanocrystals and NIR irradiation greatly enhanced the anticancer efficacy of hyperthermia and achieved a synergistic anticancer effect. The in vivo safety assessment showed that the injection dose of 10 mg kg-1 PdH0.2 nanocrystals did not cause death, and there were no changes in many blood indicators, and no damage to liver and kidney function. In a 4T1 mouse breast cancer tumor model and a B16-F10 melanoma model, the combined treatment of PdH0.2 nanocrystals and NIR irradiation showed synergistic anticancer effects with significant tumor suppressive effects compared with hyperthermia. Meanwhile, the combination group showed no significant damage to the heart, liver, spleen, lung, and kidney, indicating appropriate tissue safety and tolerability (52).

Hydrogen Gas Suppresses Tumor Formation

Reader. Drinking hydrogen-rich water has been reported to ameliorate renal injury induced by iron nitrilotriacetate (Fe-NTA) in rats, as evidenced by decreased serum creatinine and BUN levels. Hydrogen-rich water inhibited Fe-NTA-induced oxidative stress by reducing lipid peroxidation ONOO-, inhibiting the activities of NADPH oxidase and xanthine oxidase, up-regulating antioxidant catalase, and restoring renal mitochondrial function. Therefore, hydrogen treatment significantly attenuated Fe-NTA-induced inflammatory cytokines such as NF-κB, IL-6, and monocyte chemoattractant protein 1. More importantly, drinking hydrogen-rich water inhibited the expression of several cancer-related proteins, including vascular endothelial growth factor, transcription-3-phosphorylation signal converter and activator, and proliferating nuclear antigen in rats, thereby reducing renal incidence of cancer. Cell carcinomas and their inhibition lead to tumor growth. This work demonstrates that hydrogen-rich water is a promising regimen to mitigate Fe-NTA-induced renal injury and suppress early tumor events.

Nonalcoholic steatohepatitis (NASH), caused by oxidative stress from various stimuli, is one of the causes of liver cancer (94, 95). In a mouse model, administration of hydrogen-rich water decreased hepatic cholesterol and peroxisome proliferator-activated receptor-alpha (PPARα) expression and increased hepatic antioxidant activity compared with control and pioglitazone-treated groups role (96). Hydrogen-rich water showed potent inhibitory effects on inflammatory cytokines TNF-α and IL-6, oxidative stress and apoptosis biomarkers. As shown in the NASH-related hepatocarcinogenesis model, the hydrogen-rich water-treated group had a lower tumor incidence and smaller tumor volume than the control and pioglitazone-treated groups. The above results suggest that hydrogen-rich water has the potential to protect the liver and treat liver cancer (96).

Hydrogen Gas Suppresses Tumor Growth

In addition to being used as an adjuvant therapy, hydrogen can also inhibit the growth of tumors and tumor cells.

As reported in the study by Wang et al. As demonstrated on lung cancer cell lines A549 and H1975 cells, hydrogen gas inhibits cell proliferation, migration and invasion and induces significant apoptosis, such as CCK-8, wound healing, transwell assays and flow cytometry tests. Hydrogen prevents the cell cycle in the G2/M phase of both cell lines by inhibiting the expression of several cell cycle regulatory proteins, including cyclin D1, CDK4, and CDK6. Chromosome 3 (SMC3), a complex required for chromosome condensation in the cell cycle (97), is inhibited by hydrogen through ubiquitination. Importantly, an in vivo study showed that hydrogen treatment significantly inhibited tumor growth, as well as the expression of Ki-67, VEGF and SMC3. These data suggest that hydrogen could be used as a novel approach to the treatment of lung cancer (98).

Due to its physicochemical properties, the use of hydrogen in hospitals, medical institutions and laboratories is severely restricted. Reader. A solidified hydrogen-absorbing (H2) silica was designed to stably release molecular hydrogen into the cell culture medium. H2-silicic acid may inhibit cell viability in human esophageal squamous cell carcinoma (KYSE-70) in a concentration-dependent manner, whereas it requires higher doses to inhibit normal human esophageal epithelial cells (HEEpiCs), indicating its selectivity . This effect was further confirmed by apoptosis and cell migration assays in these two cell lines. Mechanistic studies suggest that H2-silicic acid exerts its anticancer effects by inducing H2O2 accumulation, cell cycle arrest, and mitochondrial pathway-mediated induction of apoptosis (72).

Hydrogen has recently been found to inhibit cancer stem cells (CSCs). Hydrogen reduces colony formation and spheroidization in human ovarian cancer cell lines Hs38.T and PA-1 cells by inhibiting the proliferation marker Ki67, the stem cell marker CD34, and angiogenesis. Hydrogen treatment significantly inhibited the proliferation, invasion and migration of Hs38.T and PA-1 cells. More importantly, hydrogen inhalation significantly suppressed tumor volume, as shown in the Hs38.T xenograft BALB/c nude mouse model (99).

Another recent study also demonstrated the role of hydrogen in inhibiting glioblastoma (GBM), the most common malignant brain tumor. In vitro studies have shown that hydrogen gas inhibits several markers associated with stem formation, thereby inhibiting glioma cell spheroidization, cell migration, invasion, and colony formation. In a rat orthotopic glioma model, twice-daily inhalation of hydrogen gas (67%) for 1 hour significantly inhibited GBM growth and improved survival, suggesting that hydrogen gas may be a promising drug for GBM treatment (100).

Discussion

Hydrogen has been recognized as a medical gas with potential to treat cardiovascular disease, inflammatory disease, neurodegenerative disease and cancer (17, 60). As a hydroxyl radical and peroxynitrite scavenger, due to its anti-inflammatory effect, hydrogen can prevent/mitigate the side effects caused by chemotherapy and radiotherapy without affecting its anticancer potential (as shown in Table 1 and Figure 1). Hydrogen can also act alone or synergistically with other therapies to inhibit tumor growth by inducing apoptosis, inhibiting CSCs-related and cell cycle-related factors, etc. (summarized in Table 1).

TABLE 1

Table 1. The Summary of various formulation, application, mechanisms of H₂ in cancer treatment.

FIGURE 1

Figure 1. Hydrogen in cancer treatment.

What’s more, in most research papers, hydrogen is safe for cancer cells and some selectivity for normal cells, which is critical for clinical trials. A clinical study is underway in China to study the role of hydrogen in cancer recovery.

So far, several methods of administration have proven available and convenient, including inhalation, drinking hydrogen-dissolved water, injecting hydrogen-saturated saline, and performing a hydrogen bath. Hydrogen-rich water is non-toxic, inexpensive, easy to administer, and can easily diffuse into tissues and cells that cross the blood-brain barrier, suggesting its potential in the treatment of brain tumors. More well-structured and sufficiently secure wearables are needed.

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