TY - JOUR
T1 - Cancer chemopreventive potential of aromathecins and phenazines, novel natural product derivatives
AU - Marler, Laura
AU - Conda-Sheridan, Martin
AU - Cinelli, Maris A.
AU - Morrell, Andrew E.
AU - Cushman, Mark
AU - Chen, Lian
AU - Huang, Ke
AU - Van Breemen, Richard
AU - Pezzuto, John M.
PY - 2010/12
Y1 - 2010/12
N2 - 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.
AB - 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.
KW - Aromathecins
KW - Cancer chemoprevention
KW - Enzyme induction
KW - Metabolism
KW - Phenazines
KW - RT-PCR
UR - http://www.scopus.com/inward/record.url?scp=78751558932&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78751558932&partnerID=8YFLogxK
M3 - Article
C2 - 21187465
AN - SCOPUS:78751558932
VL - 30
SP - 4873
EP - 4882
JO - Anticancer Research
JF - Anticancer Research
SN - 0250-7005
IS - 12
ER -