title: Arsenic hexoxide enhances TNF-α-induced anticancer effects by inhibiting NF-κB activity at a safe dose in MCF-7 human breast cancer cells.
abstract: Arsenic hexoxide (As4O6) has been used in Korean folk remedy for the treatment of cancer since the late 1980s. Evidence suggests that the anticancer effects of As4O6 are different from those of As2O3. Tumor necrosis factor-α (TNF-α) is generally increased in advanced cancer and is closely related to cancer progression, although it has cancer-killing effects. The reason is that TNF-α activates nuclear factor-κB (NF-κB) that is involved in cell proliferation, invasion, drug resistance and metastasis. In the present study, we investigated the effects of As4O6 on NF-κB activity, NF-κB-mediated cellular responses, and NF-κB-regulated gene expressions involved in metastasis at the concentrations of As4O6 where no cytotoxicity was observed. As4O6 suppressed NF-κB activation in both TNF-α-treated and control cells, and also suppressed IκB phosphorylation in a time-dependent manner, suggesting the suppression of NF-κB results, in part, from the inhibition of IκB degradation. We also confirmed the anti-NF-κB activity of As4O6 with synergism with TNF-α by augmenting caspase-8 activation. As4O6 also suppressed NF-κB activation induced by TNF-α, and some of the downstream NF-κB-regulated proteins involved in cancer proliferation, anti-apoptosis and metastasis. In conclusion, the present study demonstrated that As4O6 has anticancer properties by inhibiting NF-κB activation and NF-κB-regulated proteins at least in part through the inhibition of IκB phosphorylation, especially in the conditions of advanced cancer where TNF-α is highly secreted.
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors.forename: Won Sup
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Yun
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors.forename: Jing Nan
authors.initials: JN
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors.forename: Sang Mi
authors.initials: SM
authors.lastname: Yi
authors.affiliation: Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Surgery, Konkuk University School of Medicine, Seoul 143-701, Republic of Korea.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Chang
authors.affiliation: School of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Gon-Sup
authors.initials: GS
authors.lastname: Kim
authors.affiliation: Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors.forename: Soon Chan
authors.initials: SC
authors.lastname: Hong
authors.affiliation: Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea.
authors.forename: Woo Song
authors.initials: WS
authors.lastname: Ha
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000494:pharmacology; D001152:Arsenicals / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D053181:Caspase 8 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D001152:Arsenicals; D010087:Oxides; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; D053181:Caspase 8; D001151:Arsenic