Deoxypodophyllotoxin, a Lignan from Anthriscus sylvestris, Induces Apoptosis and Cell Cycle Arrest by Inhibiting the EGFR Signaling Pathways in Esophageal Squamous Cell Carcinoma Cells

Abstract

Deoxypodophyllotoxin (DPT) derived from Anthriscus sylvestris (L.) Hoffm has attracted considerable interest in recent years because of its anti-inflammatory, antitumor, and antiviral activity. However, the mechanisms underlying DPT mediated antitumor activity have yet to be fully elucidated in esophageal squamous cell carcinoma (ESCC). We show here that DPT inhibited the kinase activity of epidermal growth factor receptor (EGFR) directly, as well as phosphorylation of its downstream signaling kinases, AKT, GSK-3β, and ERK. We confirmed a direct interaction between DPT and EGFR by pull-down assay using DPT-beads. DPT treatment suppressed ESCC cell viability and colony formation in a time- and dose-dependent manner, as shown by MTT analysis and soft agar assay. DPT also down-regulated cyclin B1 and cdc2 expression to induce G2/M phase arrest of the cell cycle and upregulated p21 and p27 expression. DPT treatment of ESCC cells triggered the release of cytochrome c via loss of mitochondrial membrane potential, thereby inducing apoptosis by upregulation of related proteins. In addition, treatment of KYSE 30 and KYSE 450 cells with DPT increased endoplasmic reticulum stress, reactive oxygen species generation, and multi-caspase activation. Consequently, our results suggest that DPT has the potential to become a new anticancer therapeutic by inhibiting EGFR mediated AKT/ERK signaling pathway in ESCC.

Biosynthesis, total synthesis, and pharmacological activities of aryltetralin-type lignan podophyllotoxin and its derivatives

“…95 In 2020, Kwak found the DPT-induced G2/M phase arrest and apoptosis of ESCC cells by inhibiting the epidermal growth factor receptor (EGFR) mediated AKT/ERK signalling pathway. 96 To overcome the resistance to inhibitors of the epidermal growth factor receptor (EGFR), which is related to the hepatocyte growth factor receptor MET, for targeted therapy of cancer. In 2021, Kim used DPT to treat non-small cell lung cancer (NSCLC) and found that DPT could suppress the expression of p -EGFR and p-MET as well as their downs treat proteins p -ErbB3, p -AKT, and p -ERK, and induced high ROS generation.…”

Network pharmacology and molecular docking reveal the mechanisms of curcumin activity against esophageal squamous cell carcinoma

“…DNA damage and cell cycle can lead to irreversible cell cycle arrest, which induces cell apoptosis. Researchers have shown that regulation of key cell cycle proteins can induce cell cycle arrest in ESCC cells and produce anti-tumor effects ( Yao et al, 2015 ; Kwak et al, 2020 ). Prior research has shown that CUR induces cell cycle arrest in cells of acute myeloid leukemia ( Zhou et al, 2021 ), colorectal cancer cells ( Li et al, 2021 ), and pancreatic cancer cells ( Zhu and Bu, 2017 ).…”

Cinnamomi Ramulus inhibits the growth of colon cancer cells via Akt/ERK signaling pathways

“…We further provided the evidence of significant changes of the key factors involved in these pathways upon CR treatment by western blotting. In fact, mounting evidence has shown that inhibition of Akt/ERK pathways can lead to cell cycle arrest or apoptosis [25][26][27][28][29][30]. For example, a recent study showed that inhibition of Akt/ERK pathways by Hedyotis diffusa Willd (HDW) extracts could induce apoptosis in glioblastoma [25].…”