Resveratrol Potently Counteracts Quercetin Starvation‐Induced Autophagy and Sensitizes HepG2 Cancer Cells to Apoptosis

Scope Resveratrol (RSV) has been described as a potent antioxidant, antisteatotic, and antitumor compound, and it has also been identified as a potent autophagy inducer. On the other hand, quercetin (QCT) is a dietary flavonoid with known antitumor, anti‐inflammatory, and antidiabetic effects. Additionally, QCT increases autophagy. To study the hypothetical synergistic effect of both compounds, we test the combined effect of QCT and RSV on the autophagy process in HepG2 cells. Methods and results Autophagy is studied by western blotting, real‐time RT‐PCR, and cellular staining. Our results clearly indicate a bifunctional molecular effect of RSV. Both polyphenols are individually able to promote autophagy. Strikingly, when RSV is combined with QCT, it promotes a potent reduction of QCT‐induced autophagy and influences proapoptotic signaling. Conclusion RSV acts differentially on the autophagic process depending on the cellular energetic state. We further characterize the molecular mechanisms related to this effect, and we observe that AMP‐activated protein kinase (AMPK) phosphorylation, heme oxygenase 1 (HO‐1) downregulation, lysosomal membrane permeabilization (LMP), and Zinc (Zn2+) dynamics could be important modulators of such RSV‐related effects and could globally represent a promising strategy to sensitize cancer cells to QCT treatment. Quercetin (QCT), in a combined treatment with an autophagy inhibitor, may be an excellent therapeutic approach to reduce cancer cell proliferation and could be a promising strategy to sensitize cells to QCT treatment. In this sense, several synthetic autophagy inhibitors such as chloroquine or 3‐methyladenine have been shown to be successful for this purpose. In this paper, it is described that resveratrol (RSV) will act differentially on the autophagy process depending on the cellular energetic state.