Antitumor effects of extracellular alkalization: sodium bicarbonate modulates mitochondrial function, lysosomal dynamics and migration activity of cancer cells

Tumor microenvironment acidity represents a fundamental hallmark of cancer that promotes tumor progression, invasion, immune evasion, and treatment resistance.
Objective. This study investigates the antitumor mechanisms of sodium bicarbonate-induced alkalization on mouse colon adenocarcinoma CT26 cells and human melanoma cells.
Material and Methods. Cells were treated with varying sodium bicarbonate concentrations (50–119 mM) to assess effects on viability, metabolism, migration, and cell death pathways.
Results. Results demonstrated immediate concentration-dependent extracellular pH elevation that decreased after 24 hours due to metabolic adaptation. Both cell lines exhibited dose-dependent cytotoxicity with an IC50 of approximately 80–90 mM, yet minimal apoptosis was detected via Annexin V/PI staining, suggesting alternative cell death mechanisms. Sodium bicarbonate signifcantly impaired cellular migration in wound healing assays, coinciding with mitochondrial depolarization as evidenced by reduced Mito Red fuorescence. Metabolic analysis revealed increased consumption of glucose and glutamine alongside elevated lactate production, indicating metabolic reprogramming in response to alkalization stress. While lysosomal accumulation increased with treatment (measured by Lyso Green), canonical autophagy markers (LC3B and p62) showed no signifcant changes, suggesting classical autophagy pathways are not primarily involved.
Conclusion. These fndings indicate that sodium bicarbonate-induced alkalization triggers tumor cell death through mechanisms beyond conventional apoptosis and autophagy, potentially involving lysosome-mediated cell death or alkaliptosis. The study provides mechanistic insights supporting sodium bicarbonate as a potential adjuvant therapy that targets the tumor microenvironment’s acidity, with implications for enhancing conventional cancer treatments through pH modulation. Further research is needed to fully elucidate the precise cell death pathways involved.

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