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<p>The acidity of the tumor microenvironment, a major outcome of the Warburg Effect, significantly contributes to cancer progression, malignancy, and resistance to therapies. Lactate dehydrogenase, the primary enzyme driving the Warburg effect and pH regulation, presents a promising target for innovative anti-cancer drugs. This study explores the suppression of lactate production through the combined use of Galloflavin and 1-(phenylseleno)-4-(trifluoromethyl) benzene, two potent lactate dehydrogenase inhibitors, along with Sodium bicarbonate therapy. A detailed review of pH regulation mechanisms in tumor microenvironments and blood is provided. We proposed a dynamical system to describe membrane-based ion transporters in extracellular Michigan Cancer Foundation-7 (MCF-7) human breast cancer tumors and blood. The model validation and sensitivity are thoroughly analyzed. An infinite horizon multi-objective optimal control problem is formulated to manage tumor acidity while minimizing drug toxicity, proving the feasibility of such strategies. Optimal control strategies are derived and tested, demonstrating through numerical simulations that these approaches can guide oncologists in optimizing chemotherapy dosages to lower tumor extracellular pH effectively.</p>

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Multi-Objective Optimal Control of pH Levels within Tumor Microenvironment and Blood

  • 期刊论文

  • 发表日期：

    2026年4月27日

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  • Ali Emami Kerdabadi,
  • Alaeddin Malek

摘要

The acidity of the tumor microenvironment, a major outcome of the Warburg Effect, significantly contributes to cancer progression, malignancy, and resistance to therapies. Lactate dehydrogenase, the primary enzyme driving the Warburg effect and pH regulation, presents a promising target for innovative anti-cancer drugs. This study explores the suppression of lactate production through the combined use of Galloflavin and 1-(phenylseleno)-4-(trifluoromethyl) benzene, two potent lactate dehydrogenase inhibitors, along with Sodium bicarbonate therapy. A detailed review of pH regulation mechanisms in tumor microenvironments and blood is provided. We proposed a dynamical system to describe membrane-based ion transporters in extracellular Michigan Cancer Foundation-7 (MCF-7) human breast cancer tumors and blood. The model validation and sensitivity are thoroughly analyzed. An infinite horizon multi-objective optimal control problem is formulated to manage tumor acidity while minimizing drug toxicity, proving the feasibility of such strategies. Optimal control strategies are derived and tested, demonstrating through numerical simulations that these approaches can guide oncologists in optimizing chemotherapy dosages to lower tumor extracellular pH effectively.