title: Phospho-ibuprofen (MDC-917) suppresses breast cancer growth: an effect controlled by the thioredoxin system.
abstract: BACKGROUND
  We have recently synthesized phospho-ibuprofen (P-I; MDC-917), a safer derivative of ibuprofen, which has shown anti-cancer activity. We investigated its efficacy and mechanism of action in the treatment of breast cancer in preclinical models.
  
  
  METHODS
  We evaluated the anti-breast-cancer efficacy of P-I alone or incorporated into liposomes (Lipo-P-I) in human estrogen receptor-positive (MCF-7) and triple-negative, i.e., estrogen receptor-negative, progesterone receptor-negative and HER2-negative (MDA-MB231) breast cancer cell lines - as they represent the most frequent (estrogen receptor-positive) and the most difficult-to-treat (triple-negative) subtypes of breast cancer - and their xenografts in nude mice. We assessed the effect of P-I on the levels of reactive oxygen nitrogen species in response to P-I using molecular probes, on the thioredoxin system (expression and redox status of thioredoxin-1 (Trx-1) and thioredoxin reductase activity), on cyclooxygenase 2, NF-κB and mitogen-activated protein kinase cell signaling; and on the growth of xenografts with stably knocked-down Trx-1.
  
  
  RESULTS
  Compared with controls, P-I 400 mg/kg/day inhibited the growth of MDA-MB231 xenografts by 266%, while the growth of MCF-7 xenografts was inhibited 51% byP-I 300 mg/kg/day and 181% by Lipo-P-I 300 mg/kg/day. In both cell lines, P-I induced oxidative stress and suppressed the thioredoxin system (oxidized Trx-1 and decreased its expression; inhibited thioredoxin reductase activity). These changes triggered downstream redox signaling: the activity of NF-κB was suppressed and the Trx-1-ASK1 complex was dissociated, activating the p38 and JNK mitogen-activated protein kinase cascades. Trx-1 knockdown abrogated the anti-cancer effect of P-I in vitro and in vivo.
  
  
  CONCLUSIONS
  P-I is safe and effective against breast cancer. Liposomal formulation enhances its efficacy; the effect is heavily dependent on the induction of oxidative stress and the suppression of the thioredoxin system. P-I merits further evaluation as an agent for the treatment of breast cancer.
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794-8173, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Leahana M
authors.initials: LM
authors.lastname: Rowehl
authors.forename: Liqun
authors.initials: L
authors.lastname: Huang
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
authors.forename: Kvetoslava
authors.initials: K
authors.lastname: Vrankova
authors.forename: Despina
authors.initials: D
authors.lastname: Komninou
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008081:Liposomes; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010755:Organophosphates / Q000008:administration & dosage / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011485:Protein Binding; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C559491:2-(4-isobutylphenyl)propionic acid 4-(diethoxyphosphoryloxy)butyl ester; D000970:Antineoplastic Agents; D008081:Liposomes; D010755:Organophosphates; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013879:Thioredoxins; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D013880:Thioredoxin-Disulfide Reductase; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D005978:Glutathione; D007052:Ibuprofen