Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment

Abstract

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.

Warburg-associated acidification represses lactic fermentation independently of lactate, contribution from real-time NMR on cell-free systems

“…Our results suggest that the impact of lactate on the cytosolic catabolism of glucose in cancer cells relies on alternative regulation processes such as the alteration of proton exchanges at the plasma membrane 7 , signalling 50 or epigenetic modulations 51 , that are not exclusive to the cytosol and occurs on longer timescales. Contrastingly, our findings suggest that the metabolic alteration induced by acidosis in cancer 52 – 56 involves a direct interaction of protons with the cytosolic machinery of glucose catabolism, and can be observed almost instantly in isolated cytoplasmic fractions.…”

Avenue to X-ray-induced photodynamic therapy of prostatic carcinoma with octahedral molybdenum cluster nanoparticles

“…The synergy between acidosis and the PDT efficacy of 1NPs was clearly noticed, similarly to the effects of other complexes. 24 Also, significant inhibition of 1NP phototoxicity was observed under hypoxia (Fig. S6B, ESI†), highlighting the critical role of oxygen in the efficiency of PDT.…”

The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism

“…3 F–G). Since nicotinamide adenine dinucleotide phosphate (NADPH) could function as a reducing agent and play a significant role in ROS stress response [ [38] , [39] , [40] ], we measured NADPH in lymphoma cells (JeKo-1) and normal stromal NKtert cells treated with or without AF. The results showed that AF caused a moderate increase of NADPH at 2 h in both cell lines, but this increase returned to the basal level at 6 h ( Fig.…”