gms | German Medical Science

Objective: Tumor cell metabolism is dependent on the conversion of glucose to lactate even under aerobic conditions. This phenomenon, first described by Otto Warburg, is known as aerobic glycolysis and has been discussed as a possible Achilles heel for decades. After the discovery that the naturally occurring dipeptide carnosine specifically inhibits glycolysis in cells derived from glioblastoma, the question arose whether it could be used for the treatment of glioblastoma. In the present work the energy metabolism under the influence of carnosine in combination with inhibitors of oxidative phosphorylation and the tricarboxylic acid cycle (TCA) was investigated to further evaluate whether targeting the Warburg effect by carnosine may be a promising option for therapy.

Method: Cells from three glioblastoma lines were cultivated in 96 well plates and received glucose, galactose and pyruvate as different carbon sources. In addition, cells received carnosine as an inhibitor of glycolysis, CPI-613 as an inhibitor of pyruvate dehydrogenase and 2,4-dinitrophenol (DNP) as an inhibitor of oxidative phosphorylation or combinations of these compounds. After different times of cultivation ATP-production was measured and viability determined by histochemistry.

Results: ATP production in glioblastoma cells in the presence of glucose and galactose was strongly inhibited by carnosine (down to 3.6 ± 5.6% at 48 hours), almost completely killing the cells. In medium with pyruvate neither cell death nor loss of ATP production was detected under the influence of carnosine (94.0 ± 15.5 at 48 hours) but cells histochemically exhibited complete cell death and a strong loss of ATP production under the influence of DNP (0.4 ± 0.1%) and CPI-613 (38 ± 8%). Surprisingly, cells that were cultivated in pyruvate and glucose were healthy when carnosine was either combined with DNP or with CPI-613 and ATP production was comparable to that in cells without any inhibitor (DNP: 103 ± 7%; CPI-613: 77 ± 5%).

Conclusions: Carnosine has an anti-neoplastic effect on cells cultivated in glucose as the only carbon source but its effect is attenuated by the additional presence of pyruvate. This attenuation is, however, not dependent on restoring ATP production via the TCA cycle and oxidative phosphorylation. Therefore, considering exploiting aerobic glycolysis for therapy needs to take into account that cancer cells under in vivo conditions may overcome a block by means that are independent from restoring ATP production by oxidative phosphorylation.