Jatrorrhizine Exhibits an Antitumor Effect Against Gefitinib-resistant Non-small Cell Lung Cancer via Inhibiting PI3K/mTOR Phosphorylation

Epidermal growth factor receptor (EGFR) L858R/T790 M mutation-mediated gefitinib resistance (GR) is a frequent dilemma in the treatment of non-small cell lung Cancer (NSCLC). This study aimed to explore the effect of jatrorrhizine on treating GR NSCLC and its possible mechanism of action. Cell viability, migration, invasion, and Apoptosis detection were used to study the effect of jatrorrhizine on suppressing H1975 cells. Swiss Target Prediction and Traditional Chinese Medicine Database, GeneCards, and Online Mendelian Inheritance in Man databases and molecular docking were carried out to explore the targets of jatrorrhizine. Western blot was conducted to detect the effect of jatrorrhizine on inhibiting the PI3K/mTOR signaling pathway. Jatrorrhizine has a similar anti-tumor effect on inhibiting the proliferation and migration of H1975 cells. Jatrorrhizine could dose-dependently inhibit the proliferation, and invasion and promote the Apoptosis of human NSCLC cells. The PI3K-Akt signaling pathway was preliminarily predicted (Kyoto Encyclopedia of Genes and Genomes) and verified (Molecular docking) to be a critical pathway of jatrorrhizine against NSCLC. The cytotoxic assay of PI3K/mTOR Inhibitor PKI-402 on H1975 cells and ADP-Glo Kinase assay of the inhibitory effect of jatrorrhizine on PI3K kinase activity. Western blot verified that jatrorrhizine down-regulates the phosphorylation of PI3K/mTOR in H1975 cells. Our results revealed that jatrorrhizine is a potentially novel compound that inhibits GR NSCLC by inhibiting PI3K/mTOR phosphorylation.

gefitinib resistance | jatrorrhizine | mTOR | non‐small cell lung cancer | PI3K.