title: CR108, a novel vitamin K3 derivative induces apoptosis and breast tumor inhibition by reactive oxygen species and mitochondrial dysfunction.
abstract: Vitamin K3 derivatives have been shown to exert anticancer activities. Here we show a novel vitamin K3 derivative (S)-2-(2-hydroxy-3-methylbutylthio)naphthalene-1,4-dione, which is named as CR108 that induces apoptosis and tumor inhibition through reactive oxygen species (ROS) and mitochondrial dysfunction in human breast cancer. CR108 is more effective on the breast cancer cell death than other vitamin K3 derivatives. Moreover, CR108 induced apoptosis in both the non-HER-2-overexpressed MCF-7 and HER-2-overexpressed BT-474 breast cancer cells. CR108 caused the loss of mitochondrial membrane potential, cytochrome c released from mitochondria to cytosol, and cleaved PARP proteins for apoptosis induction. CR108 markedly increased ROS levels in breast cancer cells. N-acetylcysteine (NAC), a general ROS scavenger, completely blocked the CR108-induced ROS levels, mitochondrial dysfunction and apoptosis. Interestingly, CR108 increased the phosphorylation of p38 MAP kinase but conversely inhibited the survivin protein expression. NAC treatment prevented the activation of p38 MAP kinase and rescued the survivin protein levels. SB202190, a specific p38 MAP kinase inhibitor, recovered the survivin protein levels and attenuated the cytotoxicity of CR108-treated cells. Furthermore, CR108 inhibited the xenografted human breast tumor growth in nude mice. Together, we demonstrate that CR108 is a novel vitamin K3 derivative that induces apoptosis and tumor inhibition by ROS production and mitochondrial dysfunction and associates with the phosphorylation of p38 MAP kinase and the inhibition of survivin in the human breast cancer.
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30068, Taiwan.
authors.forename: Chun-Ru
authors.initials: CR
authors.lastname: Yang
authors.forename: Wei-Siang
authors.initials: WS
authors.lastname: Liao
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Wu
authors.forename: Kaliyappan
authors.initials: K
authors.lastname: Murugan
authors.forename: Chinpiao
authors.initials: C
authors.lastname: Chen
authors.forename: Jui-I
authors.initials: JI
authors.lastname: Chao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077022:Survivin; D024483:Vitamin K 3 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C586213:2-(2-hydroxy-3-methylbutylthio)naphthalene-1,4-dione; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D011725:Pyridines; D017382:Reactive Oxygen Species; D000077022:Survivin; D024483:Vitamin K 3; D045304:Cytochromes c; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D000111:Acetylcysteine
keywords: Apoptosis; Breast cancer; Mitochondria; Reactive oxygen species; Vitamin K3 derivative