Fig. 9

Effect of VOA/TMX therapy on hypoxia-induced metabolic reprogramming of serum metabolites involved in glucose metabolism. In response to hypoxia, cancer cells utilize more and more glucose which is not used in oxidative phosphorylation in mitochondria, and as a result, excess pyruvate accumulates in the cells. Accumulated pyruvate is then converted into lactate which is expelled out through MCT4 transporter into the tumor microenvironment and makes the extracellular environment exploited in various ways by the cancer cell. Treatment with VOA/TMX caused activation of PHD-2, which carries out the hydroxylation and finally proteolytic degradation of HIF-1α. Inactivation of HIF-1α ultimately reduced the glucose utilization and lactate acidosis in the tumor microenvironment. G1(normal control receives normal saline 2 ml/kg, p.o.); G2 (toxic control receives MNU 50 mg/kg, i.p); G3(MNU 50 mg/kg, i.p. + VOA 1 mg/kg, s.c.); G4 (MNU 50 mg/kg, i.p. + VOA 2 mg/kg, s,c.); G5 (MNU 50 mg/kg, i.p. + TMX 8 mg/kg, p.o.); G6 (MNU 50 mg/kg,i.p. + VOA 1 mg/kg, s.c. + TMX 1 mg/kg s.c.) and G7 (dummy control receives 3% DMSO solution s.c)