Methylene Blue in Glioblastoma (Brain Cancer) - Dr William Makis

Now look at this rare but precious article:

Glioblastoma is NOTORIOUSLY DIFFICULT to treat 2013 Poteet et al - Reversing the Warburg Effect as a Treatment for Glioblastoma. (1) "Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in Glioblastoma cell lines" "Methylene Blue decreases Glioblastoma cell proliferation and halts the cell cycle in S phase." Methylene Blue inhibits cell proliferation in both temozolomide-sensitive and -insensitive GBM cell lines (wow!!!) 

Methylene Blue Methylene blue (MB), synthesized in 1876, has been in clinical application for more than a century in diagnostic procedures and as a treatment of multiple disorders such as methemoglobinemia, malaria, ifosfamide neurotoxicity, and cyanide poisoning There is mounting evidence that MB enhances brain metabolism and exerts neuroprotective effects in multiple neurodegenerative disease models including Parkinson, Alzheimer, and Huntington disease In the current study we tested the hypothesis that reversal of the Warburg effect by MB inhibits GBM cell proliferation. More than 90 years ago, Warburg hypothesized that cancers may be caused by increased glycolysis and impaired respiration based on observations that tumor tissue actively metabolizes glucose and produces excessive lactic acid while exhibiting a comparably low respiratory rate Recent findings suggest that reinstating normal oxidative phosphorylation in cancer cells may not only inhibit cell growth and proliferation but also impair the metastatic capacity of malignant cells Acute Methylene Blue treatment dramatically increases oxygen consumption rate (OCR) and decreases extracellular acidification rate (ECAR) in U87 Glioblastoma cells. Reversal of the Warburg effect was associated with a reduction of U87 cell proliferation, evidenced by the cell growth curve, liquid colony formation, and soft agar colony formation assays CANCER NEEDS: Glioblastoma cells, like other cancers, face two major metabolic challenges, bioenergetic and biosynthetic demands of rapid cell proliferation It has been proposed that the fundamental metabolic switch may confer to cancer cells a selective advantage during growth and proliferation Glucose not only provides the major fuel for ATP synthesis through glycolysis and mitochondrial oxidative phosphorylation but glucose also provides the backbone for intermediates needed in biosynthetic pathways, including ribose sugars for nucleotides, glycerol and citrate for lipids, nonessential amino acids, and NADPH through the oxidative pentose phosphate pathway. Besides serving as the major bioenergetic hub, mitochondria also provide metabolites for macromolecule synthesis to meet the biosynthetic demand of a proliferating cancer cell. We predict that Methylene Blue reverses the Warburg effect and switches mitochondria from a biosynthetic hub back to a predominantly bioenergetic hub in GBM cells, thus decreasing metabolic intermediates and inhibiting cancer proliferation. This notion is supported by our data that MB increases ATP production, decreases NADPH, and arrests cancer cells in S phase. MB enhances oxygen consumption rate and extracellular acidification rate in glioma cells immediately after treatment. TEMOZOLOMIDE

TMZ is currently one of the primary chemotherapies for GBM TMZ is a prodrug that decomposes into a drug which disrupts GBM cell division by heavily alkylating and methylating DNA Resistance to TMZ develops when cells increase expression of certain enzymes. We tested the effect of MB on both TMZ-sensitive and TMZ-resistant GBM cell lines, U87 and T98G, respectively. As predicted, TMZ arrests U87 cell cycle at M phase. Methylene Blue induced cell cycle arrest in S phase and inhibited cell proliferation of both U87 and T98G cells. Similarly, Methylene Blue increased OCR, decreased ECAR, and activated the AMPK signaling pathway in T98G cells. These data suggested that Methylene Blue might be effective in both TMZ-sensitive and -resistant GBMs. Our study indicated that MB and TMZ arrest GBM cells at different stages of the cell cycle; thus, an additive effect on GBM proliferation might be achievable with a combination therapy of MB and TMZ. A slight additive action was indeed observed in the combination therapy of MB and TMZ in the liquid colony formation assay; therefore, we predict that combination therapy of MB and TMZ might be able to decrease the necessary dose of each drug, reducing the side effects while still achieving the maximal inhibitory effect on GBM progression. CONCLUSION:

Our current study demonstrated that Methylene Blue exerts profound action on GBM bioenergetics. Methylene Blue inhibits GBM cells proliferation and arrests the cell cycle in S phase The effect of MB on GBM proliferation intertwined with the activation of AMPK and its downstream signaling of ACC and cyclin expression By reversing the Warburg effect, Methylene Blue switches the mitochondria from a biosynthetic hub to bioenergetic hub and inhibits GBM cell proliferation. Although the inhibitory action of Methylene Blue on cancer proliferation needs further verification in vivo using different treatment paradigms, our in vitro data provide the proof of concept that reversal of Warburg effect might be a novel therapy for Glioblastoma (!) This is a very interesting study from a mechanistic view point of how Methylene Blue works on Cancer!

Sources and References: 

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC3610988/

https://x.com/MakisMD/status/1889296435729801234

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