title: 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: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.|Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors: Yi-Hua
authors: YH
authors: Lai
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors: Min-Hsuan
authors: MH
authors: Chen
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors: Sih-Yin
authors: SY
authors: Lin
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.|Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.
authors: Sheng-Yi
authors: SY
authors: Lin
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors: Yung-Hao
authors: YH
authors: Wong
authors: Department of Clinical and Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Sung-Liang
authors: SL
authors: Yu
authors: Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Huei-Wen
authors: HW
authors: Chen
authors: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Chih-Hsin
authors: CH
authors: Yang
authors: Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.|Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Gee-Chen
authors: GC
authors: Chang
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.|Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.|Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
authors: Jeremy J W
authors: JJ
authors: Chen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D018943:Anthracyclines / Q000737:chemistry / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016513:Mice, SCID; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C004977:rhodomycin; D019061:src-Family Kinases; D000077156:Gefitinib
keywords: EGFR; Src; gefitinib; lung cancer; rhodomycin A