Rhodomycin A, a novel Src-targeted compound, can suppress lung cancer cell progression via modulating Src-related pathways
Journal
Oncotarget
Journal Volume
6
Journal Issue
28
Pages
26252-26265
Date Issued
2015
Author(s)
Lai Y.-H.
Chen M.-H.
Lin S.-Y.
Lin S.-Y.
Wong Y.-H.
Chang G.-C.
Chen J.J.W.
Abstract
Src activation is involved in cancer progression and the interplay with EGFR. Inhibition of Src activity also represses the signalling pathways regulated by EGFR. Therefore, Src has been considered a target molecule for drug development. This study aimed to identify the compounds that target Src to suppress lung cancer tumourigenesis and metastasis and investigate their underlying molecular mechanisms. Using a molecular docking approach and the National Cancer Institute (NCI) compound dataset, eight candidate compounds were selected, and we evaluated their efficacy. Among them, rhodomycin A was the most efficient at reducing the activity and expression of Src in a dose-dependent manner, which was also the case for Src-associated proteins, including EGFR, STAT3, and FAK. Furthermore, rhodomycin A significantly suppressed cancer cell proliferation, migration, invasion, and clonogenicity in vitro and tumour growth in vivo. In addition, rhodomycin A rendered gefitinib-resistant lung adenocarcinoma cells more sensitive to gefitinib treatment, implying a synergistic effect of the combination therapy. Our data also reveal that the inhibitory effect of rhodomycin A on lung cancer progression may act through suppressing the Src-related multiple signalling pathways, including PI3K, JNK, Paxillin, and p130cas. These findings will assist the development of anti-tumour drugs to treat lung cancer.
SDGs
Other Subjects
Crk associated substrate protein; epidermal growth factor receptor; focal adhesion kinase; gefitinib; mitogen activated protein kinase; paxillin; phosphatidylinositol 3 kinase; protein tyrosine kinase; rhodomycin A; STAT3 protein; stress activated protein kinase; anthracycline; antineoplastic agent; antineoplastic antibiotic; protein kinase inhibitor; protein tyrosine kinase; quinazoline derivative; rhodomycin; animal cell; animal experiment; animal model; Article; cancer cell; cell invasion; cell migration; cell proliferation; cell viability; clonogenesis; colony formation; controlled study; cytotoxicity; dose response; drug mechanism; drug potency; drug potentiation; enzyme activity; enzyme inhibition; gene repression; human; human cell; in vitro study; in vivo study; information processing; lung cancer; lung carcinogenesis; lung metastasis; molecular docking; mouse; nonhuman; protein degradation; protein expression; protein targeting; tumor growth; adenocarcinoma; animal; antagonists and inhibitors; cell motion; chemical structure; chemistry; computer aided design; drug design; drug effects; drug resistance; drug screening; enzymology; genetics; Lung Neoplasms; metabolism; molecularly targeted therapy; pathology; SCID mouse; signal transduction; structure activity relation; time factor; tumor cell line; tumor invasion; Adenocarcinoma; Animals; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Movement; Cell Proliferation; Computer-Aided Design; Dose-Response Relationship, Drug; Drug Design; Drug Resistance, Neoplasm; Drug Synergism; Humans; Lung Neoplasms; Mice, SCID; Molecular Docking Simulation; Molecular Structure; Molecular Targeted Therapy; Neoplasm Invasiveness; Protein Kinase Inhibitors; Quinazolines; Signal Transduction; src-Family Kinases; Structure-Activity Relationship; Time Factors; Xenograft Model Antitumor Assays
Publisher
Impact Journals LLC
Type
journal article