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

Abstract

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 (IC₅₀ = 13.75 μM), NCI-H460 (IC₅₀ = 17.57 μM), and NCI-H292 (IC₅₀ = 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.

Keywords:

• Antitumor
• Warburg effect
• glucose
• c-Myc
• HIF-1α

Acknowledgements

The authors gratefully acknowledge the support of staff and faculties at the Key Laboratory of Evaluation on Strengthening Body Resistance to Eliminate Pathogenic Factors of Traditional Chinese Medicine in Treatment of Tumours (2020) and National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

The work was supported by the National Natural Science Foundation of China [81460618, 81860720, 81660683] and The Scientific Foundation of Double World-classes Subject Development of Jiangxi University of TCM [JXSYLXK-ZHYAO124].