Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment

International Journal of Molecular Sciences

Martina Koncošová¹  Silvie Rimpelová¹  Nikola Vrzáčková¹  Tomáš Ruml¹  Jaroslav Zelenka¹  Michaela Rumlová²  Ivana Křížová²  Petra Tomášová³  Aleš Dvořák³  Libor Vítek³ 

[1] Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic;Department of Biotechnology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic;Institute of Medical Biochemistry and Laboratory Diagnostics, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic;

关键词: tumor microenvironment;    mitochondria;    acidosis;    photodynamic therapy;    CPI-613;    tetracycline;   

DOI  :  10.3390/ijms221910790

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown