Methylene Blue for Cancer Therapy

Introduction

Methylene blue, a strong redox agent, is an organic compound with a chloride salt structure. It’s a commonly used dye that exhibits antioxidant, antimalarial, antidepressant, and cardioprotective effects. This medication is used in the primary treatment of Methemoglobinemia, Vasoplegic syndrome, Plasmodium falciparum, Ifosfamide-induced encephalopathy, and parathyroid gland mapping during parathyroidectomies. Its anti-oxidative properties highlight its potential to resist mitochondrial dysfunction and age-related decline in tissues like the brain and skin.

Cancer occurs when a cell grows uncontrollably and spreads to other body parts. Generally, cells grow and multiply to form new cells and die when old or damaged. But sometimes this procedure breaks down, leading to abnormal growth of the damaged cells that causes tumors (lumps of tissue). This could be cancerous or non-cancerous (benign). A cancerous tumor, also called a malignant tumor, invades nearby tissues and spreads to different body parts, whereas Benign tumors do not invade nearby tissues and don’t grow back after removal. However, some can be life-threatening, for instance, benign tumors in the brain.

There are more than 100 types of cancer, including Carcinoma (the most common type of cancer), Sarcoma (forms in bones and soft tissues), leukemia (blood-forming tissues of bone marrow), Lymphoma (begins in lymphocytes), Melanoma, Brain and Spinal cord tumors, and so forth.
There are several types of cancer treatment as well, including Surgery, Chemotherapy, Radiation therapy, Immunotherapy, Hormone therapy, Hyperthermia, Photodynamic therapy, Stem cell therapy, and Targeted therapy.

Recent advances in cancer research have highlighted methylene blue as a promising compound for treatment. It is now being studied for its therapeutic benefits in oncology.

Mechanism of Action of Methylene Blue as Anti-cancer agent

 

Methylene blue is a special dye that generates and increases oxygen levels in tumors. After being injected into the bloodstream, it accumulates in the tumor, where it interacts with the cancer cells, which have high levels of a molecule called NADH. This interaction causes it to reduce to its colorless form, Leucomethylene blue, in the tumor microenvironment and becomes a powerful catalyst that helps to increase oxygen levels in the tumor. As cancer cells bloom in low-oxygen surroundings, increasing oxygen levels make it harder for them to live on. This rise in oxygenation level makes cancer cells more susceptible to radiation & chemotherapy.

It also helps cancer cells switch from making energy through glycolysis to oxidative phosphorylation, which makes cancer cells more dependent on oxygen for survival. Since cancer cells are now dependent on oxygen for survival, they become more vulnerable to chemotherapy and radiation treatment. Also, these treatments work better when cancer cells have a sufficient oxygen supply. Hence, methylene blue helps to make cancer cells more vulnerable to treatments by switching how they build energy and making them dependent on oxygen for survival.

Methylene blue in anticancer photodynamic therapy

When methylene blue is used in the treatment with photodynamic therapy (PDT), it improves its efficacy, which helps against diverse types of cancer, including colorectal tumors, carcinoma, and melanoma. As it is a phenothiazine dye, Methylene blue absorbs light in the range of 630 to 680 nm, which initiates Reactive oxygen species (ROS). Further, the light energy absorbed, excites the methylene blue molecule that reacts with oxygen to stimulate ROS, i.e., singlet oxygen & free radicals. The ROS produced, damages the cancer cells by oxidizing their cellular components, such as DNA, proteins, & lipids. Later, the damaged cells undergo apoptosis (cell death) or necrosis (death of body tissue), leading to their elimination.
This accumulation of methylene blue is due to the higher metabolic rates, modified membrane permeability, and overexpression of transport proteins like p-glycoprotein in cancer cells, which facilitate the intake of methylene blue.

Evidence of Anti-cancer properties

• Methylene blue (MB) has been investigated in several studies and has shown much potential for inhibiting the growth of cancer cells, effectively in breast & ovarian tumors, when it is combined with tiny particles called maghemite nanoparticles. Singlet oxygen is produced upon light exposure, during photodynamic therapy (PDT). (https://link.springer.com/article/10.1186/s12645-021-00083-x)
• According to research issued in 2018, in the Journal of Surgical Research, MB-PDT was productive in minimizing the growth of colorectal cancer tumors in mice. (https://pubmed.ncbi.nlm.nih.gov/11154085/)
• Another phase II clinical trial published in 2019 in the Journal of Clinical Oncology investigated the use of MB-PDT in combination with chemotherapy for the treatment of pancreatic cancer and concluded that the combination was safe and endurable, with a drift towards improved overall survival.
• A phase III clinical trial is currently underway to further investigate the efficacy of this treatment in pancreatic cancer.
• Moreover, methylene blue is an effective anti-cancer agent because of its mechanism of inhibiting cell proliferation and inducing apoptosis. The journal Oncology Reports in 2017 found that it inhibits the proliferation of human ovarian cancer cells in vitro and in vivo. Further research in 2019 in the journal Cancer Cell International found that it induces apoptosis in human lung cancer cells in vitro. (https://www.mdpi.com/2072-6694/16/2/355)

Potential Benefits of Methylene Blue

Recent clinical cases have shown that Methylene blue can treat diverse cancerous & non-cancerous diseases with much effectiveness, low toxicity, and no side effects, such as:

• The use of Nanopharmaceuticals to deliver Methylene blue has been shown to enhance its efficiency in PDT. These nanoformulations can improve its bioavailability by increasing its accumulation in cancer cells and decreasing its toxicity in normal cells.
• Additionally, common therapeutic procedures like chemotherapy & radiotherapy may not promote the complete eradication of tumor cells and cause damage to nearby normal cells, which is a considerable issue considering their high cost. To the contrary, methylene blue, a low-cost drug is proven to be more effective & safe during Photodynamic Therapy.

Challenges & Limitations

• Methylene blue is observed to be effective against various types of cancer, such as colorectal tumors, carcinoma, and melanoma. Although the results are seen as less promising in breast cancer treatments & HeLa models, where there is only a limited decrease in tumor size.
• Methylene Blue-based Fluorescence imaging, which is a technique used for imaging and detecting breast tumors during surgeries, has limited penetration depth and a lack of automation.
• Furthermore, the existing studies indicate significant heterogeneity in terms of Methylene Blue sample sizes, dosing strategies, and pharmaceutical formulations, which may affect the stability of the results.
• Moreover, the inconsistency in outcome measurement methods and dosing plans across studies emphasizes the need for further research to standardize and optimize these aspects of Methylene Blue.

Future Direction of Methylene Blue

• Methylene blue has shown positive results in cancer treatments, specifically in breast cancer imaging. But still, limitations and areas for improvement are required in further research. For instance, Methylene blue’s accumulation in breast tumors is yet unclear, so there is a need to understand its mechanism and increase its effectiveness.
• Current Methylene Blue-based Fluorescence imaging systems are unable to penetrate in depth and lack automation. However, developing a more advanced system could make it more effective to detect tumors through fluorescent signals.

References

• https://pubchem.ncbi.nlm.nih.gov/compound/Methylene-Blue
• https://www.cancer.gov/about-cancer/understanding/what-is-cancer
• https://www.cancer.gov/about-cancer/treatment/types
• https://www.sciencedirect.com/science/article/pii/S1572100024000863
• https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1264961/full 
• https://link.springer.com/article/10.1186/s12645-021-00083-x
• https://journals.sagepub.com/doi/full/10.1177/1533033819894331
• https://www.mdpi.com/2673-7523/2/1/2

Disclaimer-

The information provided here is based on general knowledge, articles, research publications etc. and we do not claim the authenticity of any of the information provided above. We do not claim or suggest/advise any medical, therapeutic, health or nutritional benefits of  Methylene Blue. We do not supply or promote our Methylene Blue product for the applications which are covered by valid patents and which are not approved by the FDA.

Macsen Labs is a manufacturer and supplier of several grades of Methylene Blue such as:-

• Methylene Blue USP
• Methylene Blue Untuk Sapi
• Methylene Blue Zinc Free
• Methylene Blue BP 2000
• Methylene Blue BP 1973
• Methylthioninium Chloride BP
• Methylthioninium Chloride EP 9.0
• Methylthioninium Chloride E.P-10

Macsen Labs group’s Methylene Blue Synthesis Process granted a patent from the Indian patent office

The Indian Patent Office granted a patent to Mr Achal Agrawal, CEO of Macsen Labs, Udaipur. The title of the patent is Novel Improved Method for Synthesis of Diaminophenothiazine Compounds and it concerns a novel process for synthesising the compound Methylthioninium Chloride or Methylene Blue. Macsen Labs has now achieved a unique position by this patent and from now nobody will be able to copy this process. Read more

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