Eriodictyol Suppresses Gastric Cancer Cells via Inhibition of PI3K/AKT Pathway

Abstract

Gastric cancer (GC) is among the five most common malignancies worldwide. Traditional chemotherapy cannot efficiently treat the disease and faces the problems of side effects and chemoresistance. Polygoni orientalis Fructus (POF), with flavonoids as the main bioactive compounds, exerts anti-cancer potential. In this study, we compared the anti-GC effects of the main flavonoids from POF and investigated the anti-cancer effects of eriodictyol towards GC both in vitro and in vivo. CCK-8 assays were performed to examine the inhibitory effects of common flavonoids from POF on GC cell viability. Colony formation assays were used to determine cell proliferation after eriodictyol treatment. Cell cycle distribution was analyzed using flow cytometry. Induction of apoptosis was assessed with Annexin V/PI staining and measurement of related proteins. Anti-cancer effects in vivo were investigated using a xenograft mouse model. Potential targets of eriodictyol were clarified by network pharmacological analysis, evaluated by molecular docking, and validated with Western blotting. We found that eriodictyol exhibited the most effective inhibitory effect on cell viability of GC cells among the common flavonoids from POF including quercetin, taxifolin, and kaempferol. Eriodictyol suppressed colony formation of GC cells and induced cell apoptosis. The inhibitory effects of eriodictyol on tumor growth were also validated using a xenograft mouse model. Moreover, no obvious toxicity was identified with eriodictyol treatment. Network pharmacology analysis revealed that PI3K/AKT signaling ranked first among the anti-GC targets. The molecular docking model of eriodictyol and PI3K was constructed, and the binding energy was evaluated. Furthermore, efficient inhibition of phosphorylation and activation of PI3K/AKT by eriodictyol was validated in GC cells. Taken together, our results identify eriodictyol as the most effective anti-GC flavonoids from POF and the potential targets of eriodictyol in GC. These findings suggest that eriodictyol has the potential to be a natural source of anti-GC agents.

Artemisia argyi extracts overcome lapatinib resistance via enhancing TMPRSS2 activation in HER2‐positive breast cancer

“…Mechanistically, eriodictyol and umbelliferone reduced the phosphorylation of HER2 at Tyr1221/1222 (Figure 5A), subsequently downregulating its downstream singling pathways, including PI3K/Akt and Jak/STAT (Figure 4). The inhibitory effect of eriodictyol and umbelliferone on the PI3K/Akt pathway, resulting in the suppression of cell growth and metastasis, was also observed in glioblastoma, 68 gastric cancer, 69 and renal cell carcinoma. 70 Concurrently, these compounds activated a 32 kDa cleaved protease domain of TMPRSS2 (Figure 5A), leading to the suppression of cell proliferation and an enhanced response to lapatinib treatment.…”

Efficacy and safety of Piwei Peiyuan Prescription in the treatment of chronic atrophic gastritis: A multicenter, double-blind, double-simulated, randomized, controlled clinical trial

“…[29][30][31] A prior study unveiled that kaempferol diminished GC cell colony formation and elevated cell apoptosis by blocking the PI3K/AKT pathway. [32] Luteolin can reduce NF-κB activity, block the NF-κB pathway, and lower the expression of various proinflammatory factors such as IL-1β, IL-6, IL-8, and TNF-α. [33,34] The therapeutic effect of luteolin on GC has been validated in organoids derived from GC patients.…”

Chinese medicine in the treatment of non-alcoholic fatty liver disease based on network pharmacology: a review

“…Polygoni Orientalis Fructus (POF) is a well-known medicinal and ornamental plant with a good blood-activating effect, good antioxidant activity ( Lei, et al, 2005 ), and certain anticancer potential ( Shan, et al, 2022 ). Some scholars ( Chen, et al, 2021 ) conducted an in-depth exploration of the specific mechanism of action of POF, conducted network pharmacological analysis, and screened out a total of 18 key components in POF, including 277 potential targets.…”