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

Postbiotics are health-promoting microbial metabolites delivered as a functional food or a food supplement. They either directly influence signaling pathways of the body or indirectly manipulate metabolism and the composition of intestinal microflora. Cancer is the second leading cause of death worldwide and even though the prognosis of patients is improving, it is still poor in the substantial part of the cases. The preventable nature of cancer and the importance of a complex multi-level approach in anticancer therapy motivate the search for novel avenues of establishing the anticancer environment in the human body. This review summarizes the principal findings demonstrating the usefulness of both natural and synthetic sources of postbotics in the prevention and therapy of cancer. Specifically, the effects of crude cell-free supernatants, the short-chain fatty acid butyrate, lactic acid, hydrogen sulfide, and β-glucans are described. Contradictory roles of postbiotics in healthy and tumor tissues are highlighted. In conclusion, the application of postbiotics is an efficient complementary strategy to combat cancer.

• Klíčová slova
• GPR81, SCFA, colorectal cancer, functional food, intestinal metabolome, microbiome,
• MeSH
• beta-glukany farmakologie   MeSH
• butyráty farmakologie   MeSH
• kyselina mléčná farmakologie   MeSH
• kyseliny mastné těkavé metabolismus   farmakologie   MeSH
• lidé MeSH
• metabolom MeSH
• nádory dietoterapie   metabolismus   MeSH
• potravní doplňky mikrobiologie   MeSH
• prebiotika mikrobiologie   MeSH
• probiotika metabolismus   farmakologie   MeSH
• střevní mikroflóra účinky léků   MeSH
• sulfan farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• beta-glukany MeSH
• butyráty MeSH
• kyselina mléčná MeSH
• kyseliny mastné těkavé MeSH
• prebiotika MeSH
• sulfan MeSH

Mild constitutive hyperbilirubinemia is associated with a reduced risk of cardiovascular diseases, diabetes, and cancer. Since these pathologies are associated with aging, inflammation, and oxidative stress, we investigated whether hyperbilirubinemia interferes with ROS homeostasis in cell cultures and with inflammation, senescence, and mitochondrial dysfunction in aged rats. Human embryonic kidney cells and rat primary fibroblasts showed a dose-dependent decrease in the ratio of oxidized/reduced glutathione, intracellular H2O2 levels, and mitochondrial ROS production, with increasing bilirubin concentrations in the culture media. Compared to their normobilirubinemic siblings, aged hyperbilirubinemic Gunn rats showed significantly smaller amounts of visceral fat, better glucose tolerance, and decreased serum levels of proinflammatory cytokines TNFα, IL-1β, and IL-18. Simultaneously, livers from Gunn rats showed decreased expression of senescence markers and cell cycle inhibitors p21 and p16. Mitochondria from aged Gunn rats showed higher respiration and lower H2O2 production compared to controls. In conclusion, we demonstrated that mildly elevated serum bilirubin is generally associated with attenuation of oxidative stress and with better anthropometric parameters, decreased inflammatory status, increased glucose tolerance, fewer signs of cellular senescence, and enhanced mitochondrial function in aged rats.

• MeSH
• bilirubin krev   MeSH
• fibroblasty metabolismus   patologie   MeSH
• hyperbilirubinemie krev   patologie   MeSH
• intracelulární prostor metabolismus   MeSH
• kultivované buňky MeSH
• metabolické nemoci komplikace   patologie   MeSH
• mitochondrie metabolismus   MeSH
• potkani Gunn MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• stárnutí patologie   MeSH
• zánět komplikace   patologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bilirubin MeSH
• reaktivní formy kyslíku MeSH