The self-assembled α-lactalbumin-oleic acid complex inhibits ATP supply from both glycolysis and the TCA cycle in HepG2 cells and HepG2-bearing nude mice.

Energy metabolism has been a predominant target for anti-cancer drug development. The self-assembled anti-tumor α-lactalbumin-oleic acid complex (α-LA-OA) affects the energy metabolism of tumor cells, however, the role of targeting energy metabolism in its anti-tumor mechanism still needs to be clarified. α-LA assembled with OA to form a complex with an average diameter of 144.1 ± 7.241 nm, which is 10-fold larger than α-LA alone. Furthermore, the self-assembled α-LA-OA inhibited the ATP supply from both glycolysis and oxidative phosphorylation in HepG2 cells and HepG2-bearing nude mice. The gene expression of enzymes involved in glycolysis (HK2, aldose, PKM2, LDHB) and oxidative phosphorylation (CS, ACO2, IDH2, SDHA) was inhibited. This inhibitory effect was also evident by increased phosphorylation of AMPKα. α-LA-OA also suppressed the expression of HIF-1α and increased the expression of activated caspase-3. These findings demonstrate that the anti-tumor mechanism of α-LA-OA may be related to its inhibitory effect on the ATP supply, which then activates programmed cell death pathways. This study also indicated that α-LA-OA is a potent anti-tumor agent that targets the energy metabolism of tumor cells.