Epigallocatechin-3-gallate enhances the therapeutic effects of leptomycin B on human lung cancer a549 cells.
Our previous studies have shown Leptomycin B (LMB) is a promising antilung cancer drug. Epigallocatechin-3-gallate (EGCG) has antitumor properties but a debatable clinical application. The objective of this study is to evaluate the combination therapeutic effect of LMB and EGCG and its molecular mechanisms in human lung cancer A549 cells. Increased cytotoxicity was observed in LMB+EGCG-treated cells compared to LMB-treated cells. Elevated ROS was maximized 2 h after treatment, and LMB+EGCG-treated cells had higher ROS levels compared to LMB. N-Acetyl-L-cysteine (NAC) studies confirmed the oxidative role of LMB and/or EGCG treatment. In comparison to the control, CYP3A4, SOD, GPX1, and p21 mRNA expression levels were increased 7.1-, 2.0-, 4.6-, and 13.1-fold in LMB-treated cells, respectively, while survivin was decreased 42.6-fold. Additionally, these increases of CYP3A4, SOD, and GPX1 were significantly reduced, while p21 was significantly increased in LMB+EGCG-treated cells compared to LMB-treated cells. The qRT-PCR results for p21 and survivin were further confirmed by Western blot. Our study first shows that LMB produces ROS and is possibly metabolized by CYP3A4, GPX1, and SOD in A549 cells, and combination treatment of LMB and EGCG augments LMB-induced cytotoxicity through enhanced ROS production and the modulation of drug metabolism and p21/survivin pathways.
Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, Lubbock, TX, USA.
Meghan M
MM
Cromie
Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, Lubbock, TX, USA.
Weimin
W
Gao
D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D015854:Up-Regulation / Q000187:drug effects; D000094765:Glutathione Peroxidase GPX1
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005231:Fatty Acids, Unsaturated; D051034:Inhibitor of Apoptosis Proteins; D017382:Reactive Oxygen Species; D000077022:Survivin; D002392:Catechin; C045651:epigallocatechin gallate; D005979:Glutathione Peroxidase; D051544:Cytochrome P-450 CYP3A; D013482:Superoxide Dismutase; D000111:Acetylcysteine; C038753:leptomycin B; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human