title: Chemotherapeutic potential of diazeniumdiolate-based aspirin prodrugs in breast cancer.
abstract: Diazeniumdiolate-based aspirin prodrugs have previously been shown to retain the anti-inflammatory properties of aspirin while protecting against the common side effect of stomach ulceration. Initial analysis of two new prodrugs of aspirin that also release either nitroxyl (HNO) or nitric oxide (NO) demonstrated increased cytotoxicity toward human lung carcinoma cells compared to either aspirin or the parent nitrogen oxide donor. In addition, cytotoxicity was significantly lower in endothelial cells, suggesting cancer-specific sensitivity. To assess the chemotherapeutic potential of these new prodrugs in treatment of breast cancer, we studied their effect both in cultured cells and in a nude mouse model. Both prodrugs reduced growth of breast adenocarcinoma cells more effectively than the parent compounds while not being appreciably cytotoxic in a related nontumorigenic cell line (MCF-10A). The HNO donor also was more cytotoxic than the related NO donor. The basis for the observed specificity was investigated in terms of impact on metabolism, DNA damage and repair, apoptosis, angiogenesis and metastasis. The results suggest a significant pharmacological potential for treatment of breast cancer.
authors: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors: Debashree
authors: D
authors: Basudhar
authors: Radiation Biology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Robert C
authors: RC
authors: Cheng
authors: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors: Gaurav
authors: G
authors: Bharadwaj
authors: Radiation Biology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Lisa A
authors: LA
authors: Ridnour
authors: Radiation Biology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors: David A
authors: DA
authors: Wink
authors: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA. Electronic address: kmiranda@email.arizona.edu.
authors: Katrina M
authors: KM
authors: Miranda
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology*; D001391:Azo Compounds / Q000737:chemistry*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001391:Azo Compounds; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D011355:Prodrugs; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C452539:diazeniumdiolate; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; C039900:nitroxyl; D001241:Aspirin
keywords: Anti-inflammatory; Anticancer; Aspirin; DEA/NO; Diazeniumdiolate; IPA/NO; NONOate; NSAID; Nitric oxide; Nitroxyl