Chemotherapy is one of the main methods for malignant lung cancer treatment. However, the side effects of chemotherapy drugs are serious and it is prone to drug resistance. Therefore, multi-drug combination chemotherapy is popular in lung cancer treatment. This study found that tracheloside (TCS) was a novel inhibitor of TMEM16A which was specific high expressed in lung cancer tissues. TCS concentration dependently inhibited TMEM16A with an IC50 of 3.09 ± 0.21 μM. It inhibited lung cancer cells proliferation, migration, and induced cells apoptosis targeting TMEM16A. In addition, molecular docking combined with site-directed mutagenesis confirmed that the binding sites of TCS to TMEM16A were S387, E623, E624. Subsequently, multi-target combined drug administration was conducted based on the different drug targets of TCS and doxorubicin (DOX). Both in vitro and in vivo experiments indicated that the combined administration of low concentration of TCS and DOX achieved satisfactory anticancer effect, and it offset the side effects caused by high concentration of DOX. Therefore, TCS is a safe and efficient anticancer lead compound which can enhance the effect of DOX.
Keywords: Doxorubicin; Lung adenocarcinoma; Multi-target combination drug administration; TMEM16A; Tracheloside.
Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.