Chemotherapeutic potential of diazeniumdiolate-based aspirin prodrugs in breast cancer

Debashree Basudhar, Robert C. Cheng, Gaurav Bharadwaj, Lisa A. Ridnour, David A. Wink, Katrina M. Miranda

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)101-114
Number of pages14
JournalFree Radical Biology and Medicine
Volume83
DOIs
StatePublished - Jun 1 2015

Keywords

  • Anti-inflammatory
  • Anticancer
  • Aspirin
  • DEA/NO
  • Diazeniumdiolate
  • IPA/NO
  • NONOate
  • NSAID
  • Nitroxyl Nitric oxide

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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