Myricetin alleviates the formaldehyde-enhanced Warburg effect in tumor cells through inhibition of HIF-1α.

Myricetin is a flavonoid widely-distributed in foods with many beneficial health effects, which has been marketed in health products. Formaldehyde is an environmental carcinogen which can enhance the Warburg effect through the induction of human hypoxia-inducible factor 1 subunit alpha (HIF-1α), the primary regulator of cellular glycolysis. HIF-1α was verified as an important target in lung and ovarian tumors, which was also identified as a receptor for myricetin via molecular docking. The reinforced HIF-1α signaling, the Warburg effect and T cell suppression induced by 50 μM formaldehyde in both A549 and Caov-3 cells were dose-dependently attenuated by myricetin from 20 to 100 μM, and the attenuative effects were diminished by the stabilization of HIF-1α with deferoxamine. Exposure to 2.0 mg/m3 formaldehyde also stimulated tumor growth and elevated HIF-1α expression in tumor tissues of A549 xenograft mice, which were also alleviated by oral administration of 100 mg/kg myricetin. These results demonstrated that myricetin alleviated formaldehyde-enhanced Warburg effect in tumor cells through HIF-1α inhibition, which could be further developed as a therapeutic or complementary agent for formaldehyde-induced carcinogenesis.