title: Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models: an effect mediated by EGFR inhibition, p53 acetylation and oxidative stress.
abstract: BACKGROUND
  The anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its chemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC).
  
  
  METHODS
  Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous TNBC xenografts in nude mice. Mechanistic studies were also carried out to elucidate the mechanism of action of PA-2.
  
  
  RESULTS
  PA-2 inhibited the growth of TNBC cells in vitro more potently than aspirin. Treatment of established subcutaneous TNBC xenografts (MDA-MB-231 and BT-20) with PA-2 induced a strong growth inhibitory effect, resulting in tumor stasis (79% and 90% inhibition, respectively). PA-2, but not aspirin, significantly prevented the development of orthotopic MDA-MB-231 xenografts (62% inhibition). Mechanistically, PA-2: 1) inhibited the activation of epidermal growth factor receptor (EGFR) and suppressed its downstream signaling cascades, including PI3K/AKT/mTOR and STAT3; 2) induced acetylation of p53 at multiple lysine residues and enhanced its DNA binding activity, leading to cell cycle arrest; and 3) induced oxidative stress by suppressing the thioredoxin system, consequently inhibiting the activation of the redox sensitive transcription factor NF-κB. These molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer effect of PA-2.
  
  
  CONCLUSIONS
  Our findings demonstrate that PA-2 possesses potent chemotherapeutic efficacy against TNBC, and is also effective in its chemoprevention, warranting further evaluation as an anticancer agent.
authors.forename: Liqun
authors.initials: L
authors.lastname: Huang
authors.forename: Chi C
authors.initials: CC
authors.lastname: Wong
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Ka Wing
authors.initials: KW
authors.lastname: Cheng
authors.forename: Kvetoslava
authors.initials: K
authors.lastname: Vrankova
authors.forename: Ninche
authors.initials: N
authors.lastname: Alston
authors.forename: Nengtai
authors.initials: N
authors.lastname: Ouyang
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8173, USA. basil.rigas@stonybrookmedicine.edu.
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000378:metabolism / Q000517:prevention & control; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010755:Organophosphates / Q000008:administration & dosage / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000008:administration & dosage* / Q000378:metabolism* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D010755:Organophosphates; D016159:Tumor Suppressor Protein p53; C527365:phosphoaspirin; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D001241:Aspirin