title: Securinine disturbs redox homeostasis and elicits oxidative stress-mediated apoptosis via targeting thioredoxin reductase.
abstract: Thioredoxin reductase (TrxR) and thioredoxin (Trx) are two major components of the thioredoxin system, which plays essential roles in regulating cellular redox signaling. Mammalian TrxRs are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted considerable interests as promising targets for anticancer drugs. Securinine (SCR), a major active alkaloid lactone from the Chinese herbal medicine Securinega suffruticosa, has been established clinical success in treatment of neurological disorders. Recently, increasing evidence demonstrates that SCR has potential cytotoxicity to various types of tumor cells, which enables this old central nervous system drug as a potential cancer therapeutic agent. However, the mechanism underlying the anticancer activity of SCR is not well defined. We reported here that SCR inhibits both the purified TrxR and the enzyme in intact cells. SCR elicits accumulation of reactive oxygen species (ROS), elevation of oxidized glutathione and Trx, disturbs redox homeostasis, and eventually leads to oxidative stress-mediated HeLa cell apoptosis. Importantly, pharmacological inhibition or knockdown of TrxR sensitizes the cells to SCR treatment, underpinning the physiological significance of targeting TrxR by SCR. Our discovery discloses a novel mechanism underlying the anticancer activity of SCR and provides basic data for further development of SCR as a cancer chemotherapeutic drug.
authors: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China; School of Pharmacy, Lanzhou University, Lanzhou, Gansu 730000, China.
authors: Junmin
authors: J
authors: Zhang
authors: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
authors: Juan
authors: J
authors: Yao
authors: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
authors: Shoujiao
authors: S
authors: Peng
authors: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
authors: Xinming
authors: X
authors: Li
authors: State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China. Electronic address: fangjg@lzu.edu.cn.
authors: Jianguo
authors: J
authors: Fang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019665:Euphorbiaceae / Q000737:chemistry; D006572:Heterocyclic Compounds, Bridged-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001381:Azepines; D004791:Enzyme Inhibitors; D006572:Heterocyclic Compounds, Bridged-Ring; D007783:Lactones; D010880:Piperidines; D017382:Reactive Oxygen Species; D013880:Thioredoxin-Disulfide Reductase; C000785:securinine
keywords: Apoptosis; Oxidative stress; Reactive oxygen species; Redox homeostasis; Securinine; Thioredoxin