AntiCancer Effects of Hydrogen Gas Inhalation

AntiCancer Effects of Hydrogen Gas Inhalation by Jeffrey Dach MD

Remission of Extensive Brain Mets with Inhalation of Hydrogen Gas

Case Number One: A 51-year-old female patient was presented to medical attention with left arm pain for a month. She was diagnosed with Non-Small Cell Lung Cancer (NSCLC) with multiple brain metastases. The patient was initially treated with Gefitinib and Osimertinib with no clinical response to these two Tyrosine Kinase Inhibitor drugs.

Note: Gefitinib, an oral tyrosine kinase inhibitor (TKI) against epidermal growth factor receptor (EGFR) was FDA approved in 2015 for metastatic non-small cell lung cancer (NSCLC) whose tumors have specific mutations in the gene for the epidermal growth factor receptor (EGFR). Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor.

Following this, the patient received 28 days of Whole Brain Radiotherapy (WBRT). One week after completing the radiation therapy, the patient worsened with severe headache, vomiting, confusion, and incontinence. At this time, follow up brain MRI scan showed explosive worsening of the metastatic brain lesions (see above header image). Above Header Image: after Whole Brain Radiotherapy with Explosive Progression of Metasatic Lesions Courtesy of Xu, Kecheng, et al. “Explosive Progression of Brain Metastases from Lung Adenocarcinoma after Radiotherapy and Significant Reversal after Inhalation of Hydrogen-Oxygen Gas: A Case Report.” Ann Med Case Rep. 2022;4(1):1032.

Following this, having exhausted all conventional treatments, there was nothing left to offer this patient. As a palliative measure, the patient was treated with hydrogen gas inhalation therapy, using a mixture of 66% Hydrogen gas and 34% Oxygen, 3 liters/min, 6 hours a day. Within a week, the patient’s condition started to improve. One month later the patient was markedly improved. Remarkably, a follow up brain MRI scan at this time showed almost complete clearing of the metastatic lesions.

Above Image: Follow Up MRI Scan of Brain  2 Months after starting Hydrogen Gas Inhalation. Almost All Metastatic Lesion Have Cleared. This was durable remission on later follow up. Courtesy of Xu, Kecheng, et al. “Explosive Progression of Brain Metastases from Lung Adenocarcinoma after Radiotherapy and Significant Reversal after Inhalation of Hydrogen-Oxygen Gas: A Case Report.” Ann Med Case Rep. 2022;4(1):1032.

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Case Number Two :

Above images: Remarkable MRI scan documentation of disappearance of brain metastatic lesions in a patient with small cell lung cancer after treatment with hydrogen gas inhalation. Above images before and after hydrogen gas inhalation courtesy of Chen, Jibing, et al. “Brain metastases completely disappear in non-small cell lung cancer using hydrogen gas inhalation: A case report.” OncoTargets and therapy (2019): 11145-11151.

Thanks and credit to Daniel Stanciu, PhD for bringing this case report to my attention.(3)

Anti-Cancer Mechanism of Action

Various mechanisms of H2 gas have been proposed:

1) H2 gas is a potent antioxidant with ability to diffuse across cell membranes (4)

2) Potent  Anti-Inflammatory Effects. (5)(7)

3) Switching Metabolic Pathways  from oxidative phosphorylation to aerobic glycolysis. (5)(7)

4) The promotion of  Mitochondrial Biogenesis.(6)

5) Autophagy Inhibition may be synergistic with H2 therapy. (8)

Other Health Benefits of H2 gas

Potential health benefits of hydrogen therapy listed courtesy of Daniel Stanciu, PhD (3):

  • Benefits for acute lung injury, asthma and chronic obstructive pulmonary disease (Ref.)
  • Protects against sepsis related adverse effects such as apoptosis and necrosis of cells due to reactive oxygen species (Ref.)
  • Protects against oxidative damage (Ref.)
  • Reduces blood lactate levels (Ref.) and has a blood alkalizing effect (Ref.)
  • Prevents accumulative muscular fatigue after severe exercise (Ref.)
  • Alleviates nonalcoholic fatty liver disease (Ref.)
  • Neuroprotective Effects, improves Parkinson’s disease.(Ref.)
  • Reduces allergic reactions (Ref.)
  • Beneficial for obesity and diabetes (Ref.) (3)

Conclusion: These two case reports show remarkable clearing and sustained remission of metastatic brain lesions from Non Small Cell Lung Cancer (NSCLC) with inhalation of hydrogen gas, a treatment widely available with inexpensive home generators.

I would like to see a larger series patients with NSCLC treated with hydrogen gas inhalation at a large tertiary care cancer referral center such as MD Anderson in Houston. Also, possible synergies with repurposed drugs could be explored with preclinical studies in animal xenografts and cell cultures. For example, one wonders about synergy of hydrogen gas with autophagy inhibitors, Glycolysis inhibitors and OxPhos inhibitors in animal cancer xenograft or cell  culture models.

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Jeffrey Dach MD
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Davie, Fl 33314
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References And Links

1) Xu, Kecheng, et al. “Explosive Progression of Brain Metastases from Lung Adenocarcinoma after Radiotherapy and Significant Reversal after Inhalation of Hydrogen-Oxygen Gas: A Case Report.” Ann Med Case Rep. 2022;4(1):1032.

Rationale: For multiple brain metastases complicated by Non-Small Cell Lung Cancer (NSCLC), Whole Brain Irradiation Therapy (WBRT) is the first choice for
treatment. But little is known about the explosive progression of brain metastases caused by radiotherapy and the reversal of hydrogen gas inhalation.
Patient concerns: A 51-year-old female patient was diagnosed with NSCLC with multiple brain metastases. After receiving Gefitinib and Osimertinib without
clinical response, she received 28 days of WBRT.
Diagnosis: One week after the end of WBRT, the patient’s general condition suddenly worsened, with severe headache, vomiting, confusion, and incontinence. MRI showed that the number and size of brain metastases increased explosively. Interventions and outcomes: In the absence of any special “anti-cancer” treatment available, the patient only receives hydrogen gas inhalation therapy, inhaling a mixture of hydrogen and oxygen (66% H2 and 34% O2), 3000 ml/min, at least 6 hours a day. The patient’s condition began to improve after a week, and markedly improved after one month. A reexamination of MRI showed that more than 90% of brain metastases disappeared.

Lessons: Radiotherapy is a double-edged sword. Doctors should pay attention to the adverse effects of radiotherapy, especially for brain metastases complicated
by lung cancer. Molecular hydrogen is a therapeutic gas that can selectively scavenge toxic free radicals, its role in cancer treatment is worthy of attention and
further research.

2) Chen, Jibing, et al. “Brain metastases completely disappear in non-small cell lung cancer using hydrogen gas inhalation: A case report.” OncoTargets and therapy (2019): 11145-11151.

3) Making Tumors Drop Off: Molecular Hydrogen Author: Daniel Stanciu, PhD Last update: February 28th, 2021

Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals

4) Ohsawa, Ikuroh, et al. “Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.” Nature medicine 13.6 (2007): 688-694.
H2 selectively reduced the hydroxyl radical, the most cytotoxic of reactive oxygen species (ROS), and effectively protected cells; however, H2 did not react with other ROS, which possess physiological roles. We used an acute rat model in which oxidative stress damage was induced in the brain by focal ischemia and reperfusion. The inhalation of H2 gas markedly suppressed brain injury by buffering the effects of oxidative stress. Thus H2 can be used as an effective antioxidant therapy; owing to its ability to rapidly diffuse across membranes, it can reach and react with cytotoxic ROS and thus protect against oxidative damage.

Anti-inflammatory Effect of H2- Switching Metabolic Pathways  from oxidative phosphorylation to aerobic glycolysis.

5) Niu, Yinghao, et al. “Hydrogen attenuates allergic inflammation by reversing energy metabolic pathway switch.” Scientific Reports 10.1 (2020): 1962.

This study explored the possibility that H2 exerts its anti-inflammatory effect by
modulating energy metabolic pathway switch.
Our data demonstrates that allergic airway inflammation is associated with an energy metabolic pathway switch from oxidative phosphorylation to aerobic glycolysis.

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The promotion of mitochondrial biogenesis by H2 has been previously reported,
6) Zhang, Xiaoyue, et al. “Mitochondria: one of the vital hubs for molecular hydrogen’s biological functions.” Frontiers in Cell and Developmental Biology 11 (2023).

In most cases, compared to the disease or stress-induced model group, H2 treatment exhibited positive effects, including increased mitochondrial ATP production, enhanced mitochondrial respiration, inhibition of mPTP opening, improved MMP, reduced mtROS production, elevated complex I activity, activation of mitophagy, mitochondrial biogenesis, and mitoKATPs, etc. Although H2 has also been reported to enhance the activity of mitochondrial complex I, III, IV, and V in ovalbumin (OVA) sensitization and challenge-induced allergic airway inflammation mice (Niu et al., 2020) or lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice (Fan et al., 2022),

H2 has also been found to promote apoptosis in some types of cancers, including colon cancer and lung cancer (Runtuwene et al., 2015; Wang et al., 2018; Liu et al., 2020; Zan et al., 2022), but not in all cancers, such as liver cancer (Runtuwene et al., 2015).

Increasing evidence suggests that H2 can alleviate mitochondrial dysfunction caused by disease or external stress, as summarized in the preceding sections, the mechanisms underlying H2-induced mitochondrial responses seem to vary depending on the extent of mitochondrial damage.

Recent studies have shown that H2 is likely to exert protective effects against cardiac and neurological disorders, including myocardial infarction (Yoshida et al., 2012), diabetic peripheral neuropathy (Jiao et al., 2019), and subarachnoid hemorrhage (Zhang et al., 2021),

Dysregulated mitochondrial biogenesis has been implicated in senescence and ageing, as well as the initiation and progression of metabolic diseases, neurodegeneration and cancer (Popov, 2020).

The promotion of mitochondrial biogenesis by H2 has been previously reported, as demonstrated by increased expression of mtDNA (mtCoxII, mtCoxIV, and mtNd1) and mitochondrial biogenesis-related genes

Furthermore, H2 can stimulate mitochondrial biogenesis by enhancing the activity of enzymes involved in the mitochondrial tricarboxylic acid (TCA) cycle, mitochondrial respiratory chain and oxidative phosphorylation, including complex I, III, IV, V, as well as citrate synthase

In conclusion, in response to different degree of mitochondrial damage, H2 could alleviate mitochondrial dysfunction through diverse mechanisms of action.

In conclusion, the available evidence suggests that eukaryotic mitochondria or MROs initially possessed the capacity to metabolize H2, which gradually declined as they adapted to rising oxygen levels in their surroundings; nevertheless, many eukaryotes still retain the ability to metabolize H2 today.

despite the potential involvement of mtROS as a target of H2, the specific mitochondrial target molecules for H2 action remain unclear. .

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H2 – Potent Anti Inflammatory Response LPS mouse model –  The results suggested that hydrogen is potentially inhibitive against inflammation by inhibiting HIF-1α and IL-1α release at early occurrence. 

7) Wei, Youzhen, et al. “Potent anti-inflammatory responses: Role of hydrogen in IL-1α dominated early phase systemic inflammation.” Frontiers in Pharmacology 14 (2023): 1138762.

Methods: Inflammation in male C57/BL6J mice or RAW264.7 cells was induced with LPS, for which hydrogen was immediately administered until samples were taken. Pathological changes in lung tissue were assessed using hematoxylin and eosin (HE) staining. Levels of inflammatory factors in serum were determined using liquid protein chip. The mRNA levels of chemotactic factors in lung tissues, leukocytes, and peritoneal macrophages were measured by qRT-PCR. The expression levels of IL-1α and HIF-1α were measured by immunocytochemistry.

Results: Hydrogen alleviated LPS-induced inflammatory infiltration in the lung tissues of mice. Among the 23 inflammatory factors screened, LPS-induced upregulation of IL-1α etc. was significantly inhibited by hydrogen within 1 hour. The mRNA expression of MCP-1, MIP-1α, G-CSF, and RANTES was inhibited obviously by hydrogen at 0.5 and 1 h in mouse peritoneal macrophages. In addition, hydrogen significantly blocked LPS or H2O2-induced upregulation of HIF-1α, and IL-1α in 0.5 h in RAW264.7 cells.

Discussion: The results suggested that hydrogen is potentially inhibitive against inflammation by inhibiting HIF-1α and IL-1α release at early occurrence. The target of the inhibitive LPS-induced-inflammatory action of hydrogen is chemokines in macrophages in the peritoneal cavity. This study provides direct experimental evidence for quickly controlling inflammation with the translational application of a hydrogen-assisted protocol.

8) Liu, Leyuan, et al. “Suppression of autophagy facilitates hydrogen gas‑mediated lung cancer cell apoptosis.” Oncology Letters 20.4 (2020): 1-1.

suppression of autophagy can enhance H2 roles in promoting lung cancer cell apoptosis.

9) Fu, Zhiling, and Jin Zhang. “Molecular hydrogen is a promising therapeutic agent for pulmonary disease.” Journal of Zhejiang University-SCIENCE B 23.2 (2022): 102-122.

10) Hirano, Shin-ichi, et al. “Molecular hydrogen as a novel antitumor agent: Possible mechanisms underlying gene expression.” International Journal of Molecular Sciences 22.16 (2021): 8724.

11) Noor, Muhammad Nooraiman Zufayri Mohd, et al. “A systematic review of molecular hydrogen therapy in cancer management.” Asian Pacific journal of cancer prevention: APJCP 24.1 (2023): 37.

12) Artamonov, Mikhail Yu, et al. “Molecular Hydrogen: From Molecular Effects to Stem Cells Management and Tissue Regeneration.” Antioxidants 12.3 (2023).

organoprotective effects;
minimization of the consequences of ischemic–reperfusion lesions;
limitation of systemic inflammatory responses;
antitumor effects;
anti-aging effects;
increasing the body’s resistance to stressors of various nature;
improved exercise tolerance.

13) Chen, Ji-Bing, You-Yong Lu, and Ke-Cheng Xu. “A narrative review of hydrogen oncology: from real world survey to real world evidence.” Medical Gas Research 10.3 (2020): 130.

14) Chen, Ji-Bing, et al. ““Real world survey” of hydrogen-controlled cancer: a follow-up report of 82 advanced cancer patients.” Medical Gas Research 9.3 (2019): 115-121.

Advanced cancer treatment is a huge challenge and new ideas and strategies are required. Hydrogen exerts antioxidant and anti-inflammatory effects that may be exploited to control cancer, the occurrence and progression of which is closely related to peroxidation and inflammation. We conducted a prospective follow-up study of 82 patients with stage III and IV cancer treated with hydrogen inhalation using the “real world evidence” method. After 3-46 months of follow-up, 12 patients died in stage IV. After 4 weeks of hydrogen inhalation, patients reported significant improvements in fatigue, insomnia, anorexia and pain. Furthermore, 41.5% of patients had improved physical status, with the best effect achieved in lung cancer patients and the poorest in patients with pancreatic and gynecologic cancers. Of the 58 cases with one or more abnormal tumor markers elevated, the markers were decreased at 13-45 days (median 23 days) after hydrogen inhalation in 36.2%. The greatest marker decrease was in achieved lung cancer and the lowest in pancreatic and hepatic malignancies. Of the 80 cases with tumors visible in imaging, the total disease control rate was 57.5%, with complete and partial remission appearing at 21-80 days (median 55 days) after hydrogen inhalation. The disease control rate was significantly higher in stage III patients than in stage IV patients (83.0% and 47.7%, respectively), with the lowest disease control rate in pancreatic cancer patients. No hematological toxicity was observed although minor adverse reactions that resolved spontaneously were seen in individual cases. In patients with advanced cancer, inhaled hydrogen can improve patients’ quality-of-life and control cancer progression. Hydrogen inhalation is a simple, low-cost treatment with few adverse reactions that warrants further investigation as a strategy for clinical rehabilitation of patients with advanced cancer. The study protocol received ethical approval from the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (approval  number: Fuda20181207).

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