Pyruvate attenuates the anti-neoplastic effect of carnosine independently from oxidative phosphorylation
Abstract
Here, we investigated whether the anti-neoplastic effects of carnosine, which inhibits glycolytic ATP production, could be counteracted by ATP generation through oxidative phosphorylation driven by pyruvate. To test this, glioblastoma cells were cultured in media supplemented with glucose, galactose, or pyruvate, with or without carnosine. CPI-613 was used to block pyruvate entry into the tricarboxylic acid (TCA) cycle, while 2,4-dinitrophenol was applied to inhibit oxidative phosphorylation. Cell-based assays and histochemical analyses were conducted to assess energy metabolism and cell viability.
Measurements of ATP in cell lysates and dehydrogenase activity in live cells showed a significant reduction in viability under carnosine treatment when cells were provided with glucose or galactose. However, this effect was not observed in the presence of pyruvate. The viability of cells cultured with pyruvate was reduced by CPI-613 and 2,4-dinitrophenol, whereas no such impact was observed in glucose-supplemented conditions. Furthermore, carnosine did not affect cell viability in the presence of both glucose and pyruvate, even when oxidative phosphorylation and the TCA cycle were inhibited by 2,4-dinitrophenol or CPI-613.
In summary, glioblastoma cells can generate ATP from pyruvate via the TCA cycle and oxidative phosphorylation when glycolytic substrates are absent. Moreover, pyruvate mitigates the anti-neoplastic action of carnosine, Devimistat even when ATP production through the TCA cycle and oxidative phosphorylation is inhibited. Additionally, our findings suggest that carnosine suppresses TCA cycle activity, while 2,4-dinitrophenol enhances glycolytic ATP production.