title: Bioassay-guided isolation of dehydrocostus lactone from Saussurea lappa: A new targeted cytosolic thioredoxin reductase anticancer agent.
abstract: In a screen for mammalian thioredoxin reductases inhibitors, an MeOH extract from the roots of Saussurea lappa C.B. Clarke (Compositae) inhibited the activity of cytosolic thioredoxin reductase (TrxR1). Bioassay-guided separation of the extract led to the isolation of a new TrxR1 inhibitor, dehydrocostus lactone (DHC), a guaiane-type sesquiterpene. The content of DHC in the extract was determined to be 0.4%. DHC inhibited human cervical carcinoma HeLa cells with an IC50 of ∼12.00 μM but displayed less cytotoxicity to human immortalized normal liver cells L02. We observed that DHC killed HeLa cells through induction of apoptosis. DHC inhibited the activity of TrxR1 in HeLa cells, which elicited an accumulation of reactive oxygen species (ROS) in cells and a collapse of the intracellular redox equilibrium and eventually induced apoptosis of HeLa cells.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, People's Republic of China.
authors.forename: Meili
authors.initials: M
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, People's Republic of China; School of Pharmacy, Lanzhou University, Lanzhou, 730000, People's Republic of China.
authors.forename: Junmin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, People's Republic of China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, People's Republic of China. Electronic address: npchem@lzu.edu.cn.
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, People's Republic of China. Electronic address: fangjg@lzu.edu.cn.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Fang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry*; D017209:Apoptosis; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry*; D010084:Oxidation-Reduction; D010936:Plant Extracts / Q000737:chemistry*; D051381:Rats; D017382:Reactive Oxygen Species / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D030441:Saussurea / Q000737:chemistry*; D012717:Sesquiterpenes / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D013438:Sulfhydryl Compounds; C083030:dehydrocostus lactone; D013880:Thioredoxin-Disulfide Reductase
keywords: Apoptosis; Dehydrocostus lactone; HeLa cells; S. lappa; Thioredoxin reductases