Regulation of Acid-Base Homeostasis in Breast Cancer Cells: Therapeutic Strategies Based on Hexose and Citrate Derivatives
Abstract
Breast cancer is the most common malignancy among women and a leading cause of cancer-related mortality worldwide. A critical but often underappreciated hallmark of this disease is dysregulated acid–base homeostasis within the tumor microenvironment (TME). Driven by the Warburg effect, cancer cells preferentially utilize aerobic glycolysis, producing excessive lactate and protons. This results in extracellular acidification while maintaining a neutral-to-alkaline intracellular pH, a state that promotes proliferation, invasion, immune evasion, and resistance to therapy. Central to pH regulation are transporters and enzymes such as monocarboxylate transporters (MCT1/4), Na+/H+ exchanger (NHE1), vacuolar H+-ATPases, and carbonic anhydrases, which coordinate proton efflux and buffering. Therapeutic strategies targeting these pathways include hexose derivatives (e.g., 2-deoxy-D-glucose, D-mannose) that inhibit glycolytic flux, and citrate-based agents that buffer acidity and restore metabolic feedback inhibition. Additional approaches encompass lactate transport inhibition, bicarbonate therapy, and pH-responsive drug delivery systems. Preclinical evidence supports the efficacy of these interventions, and early clinical exploration suggests translational potential, particularly in aggressive subtypes such as triple-negative breast cancer. By disrupting the pH balance that supports tumor growth and survival, these strategies offer promising avenues for improved outcomes. This review provides a comprehensive overview of the molecular mechanisms and therapeutic opportunities for targeting acid–base regulation in breast cancer.