Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/ijms221910790
Keywords
tumor microenvironment; mitochondria; acidosis; photodynamic therapy; CPI-613; tetracycline; lactate; cancer; bioenergetics; therapy
Funding
- Czech Science Foundation [21-11688S] Funding Source: Medline
Ask authors/readers for more resources
Metabolic transformation in cancer cells leads to lactate accumulation and acidification in the tumor microenvironment, affecting cancer progression and patient prognosis. Cells adapted to acidosis are sensitive to oxidative damage, with lactate concentrations playing a role in sensitization. The drug CPI-613 can selectively eradicate acidosis-adapted cancer cells and the use of tetracycline can enhance its cytotoxic effect. Lactate metabolism in the Krebs cycle restores antioxidant capacity under acidosis.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available