Molecular targeting of retinoic acid metabolism in neuroblastoma: the role of the CYP26 inhibitor R116010 in vitro and in vivo.
Isomerisation to all-trans-retinoic acid (ATRA) is widely accepted as the key mechanism underlying the favourable clinical properties of 13-cis-retinoic acid (13cisRA). As intracellular metabolism of ATRA by CYP26 may result in clinical resistance to 13cisRA, an increase in efficacy may be achieved through modulation of this metabolic pathway. We have evaluated the effect of the CYP26 inhibitor R116010 on retinoid metabolism in neuroblastoma cell lines and a xenograft model. In neuroblastoma cells, which showed a high level of CYP26 induction in response to ATRA, R116010 selectively inhibited ATRA metabolism. In addition, siRNA-mediated knockdown of CYP26 selectively increased ATRA levels and the expression of retinoid-responsive marker genes was potentiated by R116010. Treatment of mice bearing SH-SY5Y xenografts with 13cisRA (100 mg kg(-1)) revealed substantial levels (16%) of intratumoral ATRA after 6 h, despite plasma ATRA levels representing only 1% total retinoids under these conditions. Co-administration of R116010 with 13cisRA in this mouse model resulted in significant increases in plasma ATRA and 13cisRA concentrations. Furthermore, R116010 induced significant decreases in levels of 4-oxo metabolites in hepatic tissue after co-administration with either ATRA or 13cisRA. These data suggest considerable potential for CYP26 inhibitors in the future treatment of neuroblastoma with 13cisRA.
Armstrong
J L
JL
Newcastle University, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.
Taylor
G A
GA
Thomas
H D
HD
Boddy
A V
AV
Redfern
C P F
CP
Veal
G J
GJ
D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D000072516:Retinoic Acid 4-Hydroxylase; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000378:metabolism* / Q000493:pharmacokinetics
D052160:Benzothiazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; C450682:R116010; D034741:RNA, Small Interfering; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase