Methylene Blue as a Potential Therapeutic Agent for Cancer: A Review of Mechanisms and Clinical Implications (2025)

Abstract

Methylene blue (MB), a phenothiazine-derived compound with a well-established history in medical applications, has recently garnered attention for its potential role in cancer therapy. This review examines the pharmacological properties, mechanisms of action, and emerging evidence supporting MB's anticancer effects. Through its redox-cycling capabilities, MB influences mitochondrial function, induces oxidative stress in malignant cells, and exhibits selective cytotoxicity. We further explore preclinical and clinical studies evaluating MB's efficacy and safety, while also discussing challenges and future research directions.

Introduction

Cancer remains a leading cause of morbidity and mortality worldwide, necessitating novel therapeutic approaches. Methylene blue, a heterocyclic aromatic dye initially introduced as an antimalarial agent, has demonstrated various pharmacological activities, including antimicrobial, neuroprotective, and antioxidant properties. Recently, MB has emerged as a candidate for cancer therapy due to its ability to modulate oxidative stress and mitochondrial dynamics. This review consolidates current knowledge on MB's anticancer mechanisms and its translational potential in oncology.

Pharmacological Properties of Methylene Blue

MB is a lipophilic cation that readily crosses cellular membranes and accumulates in mitochondria, where it undergoes redox cycling between its oxidized (MB) and reduced (leucomethylene blue) forms. This redox activity enables MB to modulate cellular redox states and mitochondrial electron transport chain (ETC) function. By facilitating electron transfer, MB enhances mitochondrial respiration and ATP production under physiological conditions while inducing oxidative stress under pathological conditions such as cancer.

Mechanisms of Anticancer Action

1. Mitochondrial Disruption and Oxidative Stress

   MB's ability to perturb mitochondrial function plays a central role in its anticancer effects. Cancer cells exhibit altered metabolism, characterized by increased reliance on glycolysis (Warburg effect). MB disrupts this metabolic phenotype by enhancing mitochondrial respiration and reducing glycolytic dependence, thereby impairing cancer cell survival. Additionally, MB promotes the generation of reactive oxygen species (ROS), leading to oxidative damage and apoptosis in malignant cells.

2. Induction of Apoptosis and Cell Cycle Arrest

   Several studies suggest that MB induces apoptosis via caspase activation and mitochondrial membrane depolarization. Furthermore, MB modulates key regulators of the cell cycle, including cyclins and cyclin-dependent kinases (CDKs), leading to cell cycle arrest at various phases, thereby inhibiting tumor proliferation.

3. Synergistic Effects with Conventional Therapies

   MB has demonstrated synergistic effects when combined with chemotherapy and radiation therapy. By increasing oxidative stress in cancer cells, MB enhances the cytotoxic efficacy of traditional anticancer agents while potentially reducing drug resistance. Notably, MB has been investigated as an adjuvant in photodynamic therapy (PDT) due to its photosensitizing properties, which enhance reactive oxygen species generation upon light activation.

Preclinical and Clinical Evidence

Preclinical studies have reported MB's efficacy against multiple cancer types, including glioblastoma, breast cancer, and melanoma. In vitro studies reveal MB's ability to inhibit cancer cell proliferation and induce apoptosis, whereas in vivo studies demonstrate tumor growth suppression in animal models. Although clinical data remain limited, early-phase trials suggest potential benefits, warranting further investigation through rigorous clinical studies.

Recent Studies

Recent research has provided further insights into MB's anticancer potential. A study by da Veiga Moreira et al. (2024) demonstrated that MB metabolic therapy effectively restrained in vivo ovarian tumor growth, suggesting its promise as a therapeutic approach for patients with platinum-resistant ovarian cancer.

Additionally, a systematic review by Lim (2023) supported the efficacy of MB-mediated photodynamic therapy against various cancer types, including colorectal tumors, carcinoma, and melanoma. These findings underscore the potential of MB in enhancing cancer treatment outcomes.

Furthermore, a study highlighted by Makis (2025) suggests that MB could be used as an adjunct to breast cancer surgery to eliminate microscopic residual malignant cells in the post-surgical cavity, potentially reducing recurrence rates.

Another study highlighted by Makis (2025) suggests that MB might also be effective in both TMZ (Temozolomide)-sensitive and -resistant GBMs (Glioblastomas):

"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."

Read More: Methylene Blue for Cancer

Challenges and Future Directions

Despite promising preclinical evidence, several challenges must be addressed before MB can be widely adopted in oncology. These include optimizing dosage, understanding long-term safety profiles, and elucidating potential off-target effects. Future research should focus on well-designed clinical trials to validate MB's efficacy, mechanisms, and therapeutic window in cancer treatment.

Conclusion

Methylene blue represents a promising yet under-explored agent in cancer therapy. Through its ability to modulate mitochondrial function, induce oxidative stress, and enhance conventional treatment efficacy, MB offers a unique therapeutic avenue. Further research is essential to establish its clinical utility, optimize treatment regimens, and determine its role in personalised cancer therapy.

Keywords: methylene blue, cancer therapy, oxidative stress, mitochondria, apoptosis, metabolism, chemotherapy adjuvant

References

1. Da Veiga Moreira J, Nleme N, Schwartz L, et al. Methylene Blue Metabolic Therapy Restrains In Vivo Ovarian Tumor Growth. Cancers (Basel). 2024;16(2):355. doi:10.3390/cancers16020355.
2. Lim JH. Methylene blue in anticancer photodynamic therapy: systematic review. Front Oncol. 2023;13:10568458. doi:10.3389/fonc.2023.10568458. pmc.ncbi.nlm.nih.gov
3. Shanthi P, Foes A. Abstract 2958: Evaluating the therapeutic effects of methylene blue against prostate cancer. Cancer Res (2019) 79 (13_Supplement): 2958. https://doi.org/10.1158/1538-7445.AM2019-2958
4. Makis W. Methylene Blue could be used as an adjunct to breast cancer surgery to “eliminate microscopic residual malignant cells in the post-surgical cavity.” X (formerly Twitter). 2025.
5. Ethan Poteet et al. Reversing the Warburg Effect as a Treatment for Glioblastoma. J Biol Chem. 2013 Feb 13;288(13):9153–9164. doi: 10.1074/jbc.M112.440354

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