Eupatilin, a type of flavonoid compound, has potential anti‑inflammatory and antitumor roles in gastric cancer and endometrial cancer; however, the effect of eupatilin on human esophageal cancer and the underlying molecular mechanisms remain unclear. In the present study, we investigated the antitumor effect of eupatilin on human esophageal cancer cells in vitro and in vivo. We found that eupatilin inhibited the proliferation and colony formation of esophageal cancer TE1 cells. DNA content analysis showed that eupatilin induced cell cycle arrest of TE1 cells at the G0/G1 phase. In addition, our results suggested that eupatilin suppressed TE1 cell proliferation by targeting the Akt/GSK3β and MAPK/ERK signaling cascades. Furthermore, treatment with eupatilin was found to decrease tumor volume in a TE1 xenograft mouse model, and the phosphorylation of Akt and ERK1/2 was inhibited by eupatilin in the tumor tissue. Notably, no obvious weight loss for the mice was detected. In conclusion, the present results indicate that the antiproliferative effect of eupatilin on esophageal cancer TE1 cells is associated with inhibition of the Akt and ERK pathways.

Abstract. Aberrant AKT and extracellular signal-regulated kinase (ERK) activation is often observed in various human cancers. Both AKT and ERK are important in the phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase kinase/ERK signaling pathways, which play vital roles in cell proliferation, differentiation and survival. Compounds that are able to block these pathways have therefore a promising use in cancer treatment and prevention. The present study revealed that AKT and ERK are activated in esophageal cancer TE1 cells. Aloe-emodin, an anthraquinone present in aloe latex, can suppress TE1 cell proliferation and anchor-independent cell growth. Aloe-emodin can also reduce the number of TE1 cells in S phase. Protein analysis indicated that aloe-emodin inhibits the phosphorylation of AKT and ERK in a dose-dependent manner. Overall, the present data indicate that aloe-emodin can suppress TE1 cell growth by inhibiting AKT and ERK phosphorylation, and suggest its clinical use for cancer therapy.

Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that play fundamental roles in regulation of multiple signaling pathways, including cell proliferation, survival and cell cycle. Increasing evidence has shown that abnormal activation of PI3K pathway contributes to tumorigenesis and progression of various malignant tumors. Therefore, it is an attractive target of chemoprevention and chemotherapy. Eupatilin, a natural flavone compound extracted from Artemisia vulgaris, has antitumor and anti-inflammation efficacy. However, the direct target(s) of eupatilin in cancer chemoprevention are still elusive. In the present study, we reported eupatilin suppressed JB6 cell proliferation and its EGF-induced colony formation. Eupatilin attenuated phosphorylation of PI3K downstream signaling molecules. Downregulation of cyclin D1 expression and arresting in G1 phase were induced through eupatilin treatment. Furthermore, we found it could bind to the p110α, a catalytic subunit of PI3K, by computational docking methods. Pull down assay outcomes also verified the binding of eupatilin with PI3K. Taken together, our results suggest that epatilin is a potential chemopreventive agent in inhibition of skin cell transformation by targeting PI3K.