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

0551327 - MBÚ 2022 RIV CH eng J - Článek v odborném periodiku
Koncošová, M. - Vrzáčková, N. - Křížová, I. - Tomášová, Petra - Rimpelová, S. - Dvořák, A. - Vítek, L. - Rumlová, M. - Ruml, T. - Zelenka, J.
Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment.
International Journal of Molecular Sciences. Roč. 22, č. 19 (2021), č. článku 10790. E-ISSN 1422-0067
Institucionální podpora: RVO:61388971
Klíčová slova: tumor microenvironment * mitochondria * acidosis * photodynamic therapy * cpi-613 * tetracycline * lactate * cancer * bioenergetics * therapy
Obor OECD: Microbiology
Impakt faktor: 6.208, rok: 2021
Způsob publikování: Open access
https://www.mdpi.com/1422-0067/22/19/10790

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.
Trvalý link: http://hdl.handle.net/11104/0326775