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.

• Klíčová slova
• CPI-613, acidosis, bioenergetics, cancer, lactate, mitochondria, photodynamic therapy, tetracycline, therapy, tumor microenvironment,
• MeSH
• acidóza patofyziologie   MeSH
• citrátový cyklus účinky léků   MeSH
• energetický metabolismus MeSH
• fyziologická adaptace MeSH
• glukosa metabolismus   MeSH
• glykolýza MeSH
• kapryláty farmakologie   MeSH
• koncentrace vodíkových iontů MeSH
• kyselina mléčná metabolismus   MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   patologie   MeSH
• nádorové buňky kultivované MeSH
• nádorové mikroprostředí * MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• oxidační stres MeSH
• protinádorové látky farmakologie   MeSH
• sulfidy farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• devimistat MeSH Prohlížeč
• glukosa MeSH
• kapryláty MeSH
• kyselina mléčná MeSH
• protinádorové látky MeSH
• sulfidy MeSH