Ethyl gallate as a novel ERK1/2 inhibitor suppresses patient‐derived esophageal tumor growth

Abstract

Ethyl gallate (EG) is a phenolic compound that is isolated from walnut kernels, euphorbia fischeriana, and galla rhois. It has been reported to exhibit antioxidant and anticancer activities. However, EG's effects on esophageal cancer have not yet been investigated.In the present study, we report that EG is a novel ERK1/2 inhibitor that suppresses esophageal cancer growth in vitro and in vivo. EG suppressed anchorage-dependent and -independent esophageal cancer cell growth. The results of in vitro kinase assays and cell-based assays indicated that EG directly binds to and inhibits ERK1 and ERK2 activities and their downstream signaling. Additionally, EG's inhibitory effect on cell growth is resistant to the re-activation of ERK1/2. EG increased G2/M phase cell cycle by reducing the expression of cyclin A2 and cyclin B1. The compound also stimulated cellular apoptosis through the activation of caspases 3 and 7 and inhibition of BCL2 expression. Notably, EG inhibited patient-derived esophageal tumor growth in an in vivo mouse model. These results indicate that EG is an ERK1/2 inhibitor that could be useful for treating esophageal cancer. K E Y W O R D S ERK1/2, esophageal cancer, ethyl gallate, patient-derived xenograft

Potential of Thai Herbal Extracts on Lung Cancer Treatment by Inducing Apoptosis and Synergizing Chemotherapy

“…In previous studies ethyl gallate induces HL-60 apoptosis via the mitochondria-mediated pathway. It also suppresses proliferation and invasion of breast cancer via Akt-NF-kB signaling, and inhibits patient-derived esophageal tumor growth in an in vivo mouse model via ERK1/2 inhibition [52][53][54]. Therefore, the two most abundant compounds, pyrogallol and ethyl gallate, might possess significant anticancer activity in EE.…”

Purpurogallin is a novel mitogen‐activated protein kinase kinase 1/2 inhibitor that suppresses esophageal squamous cell carcinoma growth in vitro and in vivo

“…Previously, JB6 mouse epithelial cells have been used to identify potential molecular targets of selected compounds, and MAPK and V‐akt murine thymoma viral oncogene homolog (AKT) signaling is strongly activated by hydrogen peroxide (H 2 O 2 ), 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA), or EGF stimulation . To identify potential molecular targets of purpurogallin, we first investigated whether purpurogallin could affect H 2 O 2 ‐induced signaling proteins in JB6 cells.…”

Patient-derived xenograft: a developing tool for screening biomarkers and potential therapeutic targets for human esophageal cancers

“…Ethyl gallate (EG) is a natural phenolic compound obtained from herbs like Galla Rhois, Longan and Acacia nilotica Wild [ 108 – 110 ]. EG directly interacts with ERK1/2 and negatively regulated ERK1/2 activities in ESCC cells, leading to the inhibition of cell proliferation, interruption of cell cycle, and increase of cell apoptosis [ 111 ]. In ESCC PDX models, EG administration suppressed tumor growth via the inactivation of ERK1/2 [ 111 ].…”