Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment
| Autor: | Jaroslav Zelenka, Ivana Křížová, Michaela Rumlová, Aleš Dvořák, Nikola Vrzáčková, Petra Tomášová, Libor Vítek, Tomáš Ruml, Silvie Rimpelová, Martina Koncošová |
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| Rok vydání: | 2021 |
| Předmět: |
Cell
Mitochondrion Pharmacology medicine.disease_cause bioenergetics chemistry.chemical_compound Neoplasms Tumor Cells Cultured Tumor Microenvironment Biology (General) Spectroscopy Acidosis General Medicine Hydrogen-Ion Concentration Adaptation Physiological Computer Science Applications Mitochondria CPI-613 Chemistry medicine.anatomical_structure photodynamic therapy acidosis medicine.symptom Caprylates Glycolysis Nicotinamide adenine dinucleotide phosphate QH301-705.5 Citric Acid Cycle Antineoplastic Agents Sulfides Catalysis Article Inorganic Chemistry medicine Humans cancer Lactic Acid Physical and Theoretical Chemistry QD1-999 Molecular Biology tetracycline Tumor microenvironment lactate therapy Organic Chemistry Metabolism Oxidative Stress Glucose chemistry Cancer cell Energy Metabolism Oxidative stress |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 10790, p 10790 (2021) Volume 22 Issue 19 |
| ISSN: | 1422-0067 |
| Popis: | Metabolic transformation of cancer cells leads to the accumulation of lactate and significant acidification in the tumor microenvironment. Both lactate and acidosis have a well-documented impact on cancer progression and negative patient prognosis. Here, we report that cancer cells adapted to acidosis are significantly more sensitive to oxidative damage induced by hydrogen peroxide, high-dose ascorbate, and photodynamic therapy. Higher lactate concentrations abrogate the sensitization. Mechanistically, acidosis leads to a drop in antioxidant capacity caused by a compromised supply of nicotinamide adenine dinucleotide phosphate (NADPH) derived from glucose metabolism. However, lactate metabolism in the Krebs cycle restores NADPH supply and antioxidant capacity. CPI-613 (devimistat), an anticancer drug candidate, selectively eradicates the cells adapted to acidosis through inhibition of the Krebs cycle and induction of oxidative stress while completely abrogating the protective effect of lactate. Simultaneous cell treatment with tetracycline, an inhibitor of the mitochondrial proteosynthesis, further enhances the cytotoxic effect of CPI-613 under acidosis and in tumor spheroids. While there have been numerous attempts to treat cancer by neutralizing the pH of the tumor microenvironment, we alternatively suggest considering tumor acidosis as the Achilles’ heel of cancer as it enables selective therapeutic induction of lethal oxidative stress. |
| Databáze: | OpenAIRE |
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