Rhodomycin A, a novel Src-targeted compound, can suppress lung cancer cell progression via modulating Src-related pathways.

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.

• Authors: Yi-Hua Lai, Min-Hsuan Chen, Sih-Yin Lin, Sheng-Yi Lin, Yung-Hao Wong, Sung-Liang Yu, Huei-Wen Chen, Chih-Hsin Yang, Gee-Chen Chang, Jeremy J W Chen
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 28 Pg. 26252-65 (Sep 22 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26312766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracyclines
• Antibiotics, Antineoplastic
• Protein Kinase Inhibitors
• Quinazolines
• rhodomycin
• src-Family Kinases
• Gefitinib

Topics

• Adenocarcinoma (drug therapy, enzymology, genetics, pathology)
• Adenocarcinoma of Lung
• Animals
• Anthracyclines (chemistry, pharmacology)
• Antibiotics, Antineoplastic (chemistry, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Computer-Aided Design
• Dose-Response Relationship, Drug
• Drug Design
• Drug Resistance, Neoplasm
• Drug Synergism
• Gefitinib
• Humans
• Lung Neoplasms (drug therapy, enzymology, genetics, pathology)
• Mice, SCID
• Molecular Docking Simulation
• Molecular Structure
• Molecular Targeted Therapy
• Neoplasm Invasiveness
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)
• Structure-Activity Relationship
• Time Factors
• Xenograft Model Antitumor Assays
• src-Family Kinases (antagonists & inhibitors, genetics, metabolism)