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Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment
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SYSNO ASEP 0551327 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment Tvůrce(i) Koncošová, M. (CZ)
Vrzáčková, N. (CZ)
Křížová, I. (CZ)
Tomášová, Petra (MBU-M)
Rimpelová, S. (CZ)
Dvořák, A. (CZ)
Vítek, L. (CZ)
Rumlová, M. (CZ)
Ruml, T. (CZ)
Zelenka, J. (CZ)Číslo článku 10790 Zdroj.dok. International Journal of Molecular Sciences. - : MDPI
Roč. 22, č. 19 (2021)Poč.str. 20 s. Jazyk dok. eng - angličtina Země vyd. CH - Švýcarsko Klíč. slova tumor microenvironment ; mitochondria ; acidosis ; photodynamic therapy ; cpi-613 ; tetracycline ; lactate ; cancer ; bioenergetics ; therapy Vědní obor RIV EE - Mikrobiologie, virologie Obor OECD Microbiology Způsob publikování Open access Institucionální podpora MBU-M - RVO:61388971 UT WOS 000713203300001 EID SCOPUS 85116495539 DOI 10.3390/ijms221910790 Anotace 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. Pracoviště Mikrobiologický ústav Kontakt Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Rok sběru 2022 Elektronická adresa https://www.mdpi.com/1422-0067/22/19/10790
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