{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T15:20:28Z","timestamp":1788880828708,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T00:00:00Z","timestamp":1633478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["21-11688S"],"award-info":[{"award-number":["21-11688S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2019 heel of cancer as it enables selective therapeutic induction of lethal oxidative stress.<\/jats:p>","DOI":"10.3390\/ijms221910790","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T16:23:58Z","timestamp":1633623838000},"page":"10790","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment"],"prefix":"10.3390","volume":"22","author":[{"given":"Martina","family":"Konco\u0161ov\u00e1","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikola","family":"Vrz\u00e1\u010dkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0497-4924","authenticated-orcid":false,"given":"Ivana","family":"K\u0159\u00ed\u017eov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Tom\u00e1\u0161ov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic"},{"name":"Institute of Microbiology, The Czech Academy of Sciences, 140 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3008-1396","authenticated-orcid":false,"given":"Silvie","family":"Rimpelov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1285-6928","authenticated-orcid":false,"given":"Ale\u0161","family":"Dvo\u0159\u00e1k","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5318-0151","authenticated-orcid":false,"given":"Libor","family":"V\u00edtek","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic"},{"name":"4th Department of Internal Medicine, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 120 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5645-8227","authenticated-orcid":false,"given":"Michaela","family":"Rumlov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5698-4366","authenticated-orcid":false,"given":"Tom\u00e1\u0161","family":"Ruml","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-8037","authenticated-orcid":false,"given":"Jaroslav","family":"Zelenka","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The warburg effect: How does it benefit cancer cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem. 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