α-Hederin inhibits the growth of lung cancer A549 cells in vitro and in vivo by decreasing SIRT6 dependent glycolysis

CONTEXT: α-Hederin, a potent bioactive compound of Pulsatilla chinensis (Bunge) Regel (Ranunculaceae), has many pharmacological uses, but its effect on cancer cell metabolism is still unclear. OBJECTIVE: To elucidate the role of α-hederin in the glucose metabolism of lung cancer cells. MATERIALS AND METHODS: Cell Counting Kit 8 and colony formation assays were employed to assess the antiproliferative effects of α-hederin. Glucose uptake, ATP generation, and lactate production were measured. Glycolysis-related proteins were detected using western blotting, and a sirtuin 6 (SIRT6) inhibitor was used to verify A549 cell proliferation. Sixty male BALB/c nude mice were divided into normal control, 5-FU (25 mg/kg), and α-hederin (5 and 10 mg/kg) groups to assess the antitumor effect for 32 days. Glycolysis-related protein expression was evaluated using immunohistochemical analysis. RESULTS: α-Hederin inhibited A549 (IC(50) = 13.75 μM), NCI-H460 (IC(50) = 17.57 μM), and NCI-H292 (IC(50) = 18.04 μM) proliferation; inhibited glucose uptake and ATP generation; and reduced lactate production. Furthermore, α-hederin (10 and 15 μM) markedly inhibited hexokinase 2, glucose transporter 1, pyruvate kinase M2, lactate dehydrogenase A, monocarboxylate transporter, c-Myc, hypoxia-inducible factor-1α, and activated SIRT6 protein expression. Using a SIRT6 inhibitor, we demonstrated that α-hederin inhibits glycolysis by activating SIRT6. A tumour xenograft mouse model of lung cancer confirmed that α-hederin (5 and 10 mg/kg) inhibits lung cancer growth by inhibiting glycolysis in vivo. DISCUSSION AND CONCLUSIONS: α-Hederin inhibits A549 cell growth by inhibiting SIRT6-dependent glycolysis. α-Hederin might serve as a potential agent to suppress cancer.