title: LW-214, a newly synthesized flavonoid, induces intrinsic apoptosis pathway by down-regulating Trx-1 in MCF-7 human breast cells.
abstract: In this study, the anticancer effect of LW-214, a newly synthesized flavonoid, against MCF-7 human breast cancer cells and the underlying mechanisms were investigated. LW-214 triggered the mitochondrial apoptotic pathway by increasing Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (ΔΨm) and caspase-9 activation, degradation of poly (ADP-ribose) polymerase (PARP), cytochrome c (Cyt c) release and apoptosis-inducing factor (AIF) transposition. Further research revealed that both the reactive oxygen species (ROS) generation and the apoptosis signal regulating kinase 1 (ASK1) activation by LW-214 were induced by down-regulating the thioredoxin-1 (Trx-1) expression. The ROS elevation and ASK1 activation induced a sustained phosphorylation of c-Jun N-terminal kinase (JNK), while SP600125, as known as JNK inhibitor, almost reversed LW-214-induced apoptosis in MCF-7 cells. Overexpression of Trx-1 in MCF-7 cells attenuated LW-214-mediated apoptosis as well as the JNK activation and reversed the expression of mitochondrial apoptosis-related protein. Accordingly, the in vivo study showed that LW-214 exhibited a potential antitumor effect in BALB/c species mice inoculated MCF-7 tumor with low systemic toxicity, and the mechanism was the same as in vitro study. Taken together, these findings indicated that LW-214 may down-regulated Trx-1 function, causing intracellular ROS generation and releasing the ASK1, and lead to JNK activation, which consequently induced the mitochondrial apoptosis in vitro and in vivo.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Hanchi
authors.initials: H
authors.lastname: Miao
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Libin
authors.initials: L
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address: zhaolicpu@126.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address: anticancer_drug@163.com.
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; C491203:TXN protein, human; D013879:Thioredoxins
keywords: ASK1; Apoptosis; Chrysin (PubChem CID: 5281607); DAPI (PubChem CID: 2954); DMSO (PubChem CID: 679); JNK; LW-214; MTT formazan (PubChem CID: 16218671); NAC (PubChem CID: 12035); Paclitaxcel (PubChem CID: 36314); ROS; Rotenone (PubChem CID: 6758); Trx-1