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.
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Authors | Debashree Basudhar, Robert C Cheng, Gaurav Bharadwaj, Lisa A Ridnour, David A Wink, Katrina M Miranda |
Journal | Free radical biology & medicine
(Free Radic Biol Med)
Vol. 83
Pg. 101-14
(Jun 2015)
ISSN: 1873-4596 [Electronic] United States |
PMID | 25659932
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
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Copyright | Copyright © 2015 Elsevier Inc. All rights reserved. |
Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- Azo Compounds
- Nitric Oxide Donors
- Nitrogen Oxides
- Prodrugs
- RNA, Messenger
- Reactive Oxygen Species
- diazeniumdiolate
- Nitric Oxide
- Cyclooxygenase 2
- nitroxyl
- Aspirin
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Topics |
- Adenocarcinoma
(drug therapy, metabolism, pathology)
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(chemistry, pharmacology)
- Apoptosis
(drug effects)
- Aspirin
(chemistry, pharmacology)
- Azo Compounds
(chemistry)
- Blotting, Western
- Breast Neoplasms
(drug therapy, metabolism, pathology)
- Cell Movement
(drug effects)
- Cell Proliferation
(drug effects)
- Cyclooxygenase 2
(metabolism)
- Female
- Humans
- Mice
- Nitric Oxide
(metabolism)
- Nitric Oxide Donors
(pharmacology)
- Nitrogen Oxides
(metabolism)
- Prodrugs
(pharmacology)
- RNA, Messenger
(genetics)
- Reactive Oxygen Species
(metabolism)
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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