title: Design and discovery of novel quinazolinedione-based redox modulators as therapies for pancreatic cancer.
abstract: BACKGROUND
  Altered cellular bioenergetics and oxidative stress are emerging hallmarks of most cancers including pancreatic cancer. Elevated levels of intrinsic reactive oxygen species (ROS) in tumors make them more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm their adaptive antioxidant capacity and trigger ROS-mediated cell death. Recently, we have discovered a novel class of quinazolinediones that exert their cytotoxic effects by modulating ROS-mediated signaling.
  
  
  METHODS
  Cytotoxic potential was determined by colorimetric and colony formation assays. An XF24 Extracellular Flux Analyzer, and colorimetric and fluorescent techniques were used to assess the bioenergetics and oxidative stress effects, respectively. Mechanism was determined by Western blots.
  
  
  RESULTS
  Compound 3a (6-[(2-acetylphenyl)amino]quinazoline-5,8-dione) was identified through a medium throughput screen of ~1000 highly diverse in-house compounds and chemotherapeutic agents for their ability to alter cellular bioenergetics. Further structural optimizations led to the discovery of a more potent analog, 3b (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) that displayed anti-proliferative activities in low micromolar range in both drug-sensitive and drug-resistant cancer cells. Treatment with 3b causes Akt activation resulting in increased cellular oxygen consumption and oxidative stress in pancreatic cancer cells. Moreover, oxidative stress induced by 3b promoted activation of stress kinases (p38/JNK) resulting in cancer cell death. Treatment with antioxidants was able to reduce cell death confirming ROS-mediated cytotoxicity.
  
  
  CONCLUSIONS
  In conclusion, our novel quinazolinediones are promising lead compounds that selectively induce ROS-mediated cell death in cancer cells and warrant further preclinical studies.
  
  
  CONCLUSIONS
  Since 3b (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) exerts Akt-dependent ROS-mediated cell death, it might provide potential therapeutic options for chemoresistant and Akt-overexpressing cancers.
authors: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA, USA.
authors: Divya
authors: D
authors: Pathania
authors: Mario
authors: M
authors: Sechi
authors: Michele
authors: M
authors: Palomba
authors: Vanna
authors: V
authors: Sanna
authors: Francesco
authors: F
authors: Berrettini
authors: Angela
authors: A
authors: Sias
authors: Laleh
authors: L
authors: Taheri
authors: Nouri
authors: N
authors: Neamati
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: C586905:6-((2-acetylphenyl)amino)quinazoline-5,8-dione; D052999:Quinazolinones; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt
keywords: 1,5-bis{[2-(di-methylamino) ethyl]amino}-4,8-dihydroxyanthracene-9,10-dione; 3-Nitrooxyphenyl acetylsalicylate; 5-chloromethylfluorescein diacetate; Anticancer compounds; CMFDA; DMEM; DMSO; DNA; DPBS; DRAQ5®; Dulbecco's Modified Eagle Medium; Dulbecco's Phosphate Buffered Saline; EDTA; FoxO3a; GAPDH; GSH; JNK; MnSOD; N-acetylcysteine; NAC; NAD(P)H dehydrogenase (quinone) 1; NADPH; NADPH oxidase; NO-ASA; NOX1; NQO1; OCR; Oxidative stress in cancer cells; RIPA buffer; ROS; ROS-mediated cell death; RPMI-1640; Radio-Immunoprecipitation Assay buffer; Redox regulation; Roswell Park Memorial Institute-1640; Small molecule drug discovery; c-Jun N-terminal kinase; deoxyribonucleic acid; dimethyl sulfoxide; ethylene diaminetetraacetic acid; forkhead box transcription factor 3a; glutathione (reduced); glyceraldehyde 3-phosphate dehydrogenase; manganese superoxide dismutase, MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; nicotinamide adenine dinucleotide phosphate (reduced); oxygen consumption rate; reactive oxygen species