Cancer chemopreventive potential of aromathecins and phenazines, novel natural product derivatives

Laura Marler, Martin Conda-Sheridan, Maris A. Cinelli, Andrew E. Morrell, Mark Cushman, Lian Chen, Ke Huang, Richard Van Breemen, John M. Pezzuto

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

In the search for agents with cancer chemopreventive potential, 14-chloromethyl-12H-5,11adiazadibenzo[b,h]fiuoren-11-one (compound 1), originally synthesized as a potential topoisomerase I inhibitor, and 2,4-dibromo-1-hydroxyphenazine (compound 2), an analog of a substance found in the marine bacteria Streptomyces CNS284, were found to significantly enhance NADP(H):quinone oxidoreductase 1 (QR1), glutathione S-transferase (GST), and glutathione (GSH) levels in cell culture. However, following a short-term absorption study, analyses of livers from the treatment groups did not reveal a significant increase in QR1 or GST activity, or GSH levels. This was consistent with RT-PCR analyses of tissue samples. The compounds were absorbed, as judged by LCIMS analyses of serum and tissue samples, although levels were well below the concentrations required to mediate in vitro responses. Metabolites of compound 2 formed in vitro by human liver microzones were characterized using high resolution tandem mass spectrometry. In sum, the in vivo activity of these compounds appears to be diminished by low bioavailability, but this experimental approach indicates the importance of systematic biomarker investigation.

Original languageEnglish (US)
Pages (from-to)4873-4882
Number of pages10
JournalAnticancer Research
Volume30
Issue number12
Publication statusPublished - Dec 1 2010

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Keywords

  • Aromathecins
  • Cancer chemoprevention
  • Enzyme induction
  • Metabolism
  • Phenazines
  • RT-PCR

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Marler, L., Conda-Sheridan, M., Cinelli, M. A., Morrell, A. E., Cushman, M., Chen, L., ... Pezzuto, J. M. (2010). Cancer chemopreventive potential of aromathecins and phenazines, novel natural product derivatives. Anticancer Research, 30(12), 4873-4882.