Inhibition of mitochondrial metabolism leads to selective eradication of cells adapted to acidic microenvironment
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22330%2F21%3A43922533" target="_blank" >RIV/60461373:22330/21:43922533 - isvavai.cz</a>
Result on the web
<a href="http://file:///C:/Users/kasparkh/AppData/Local/Temp/ijms-22-10790.pdf" target="_blank" >http://file:///C:/Users/kasparkh/AppData/Local/Temp/ijms-22-10790.pdf</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3390/ijms221910790" target="_blank" >10.3390/ijms221910790</a>
Alternative languages
Result language
angličtina
Original language name
Inhibition of mitochondrial metabolism leads to selective eradication of cells adapted to acidic microenvironment
Original language description
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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/GA21-11688S" target="_blank" >GA21-11688S: Core-shell nanoparticles for targeted X-ray-induced photodynamic therapy</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
International Journal of Molecular Sciences
ISSN
1661-6596
e-ISSN
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Volume of the periodical
22
Issue of the periodical within the volume
19
Country of publishing house
CH - SWITZERLAND
Number of pages
20
Pages from-to
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UT code for WoS article
000713203300001
EID of the result in the Scopus database
2-s2.0-85116495539