title: Inhibition of all-TRANS-retinoic acid metabolism by R116010 induces antitumour activity.
abstract: All-trans-retinoic acid is a potent inhibitor of cell proliferation and inducer of differentiation. However, the clinical use of all-trans-retinoic acid in the treatment of cancer is significantly hampered by its toxicity and the prompt emergence of resistance, believed to be caused by increased all-trans-retinoic acid metabolism. Inhibitors of all-trans-retinoic acid metabolism may therefore prove valuable in the treatment of cancer. In this study, we characterize R116010 as a new anticancer drug that is a potent inhibitor of all-trans-retinoic acid metabolism. In vitro, R116010 potently inhibits all-trans-retinoic acid metabolism in intact T47D cells with an IC(50)-value of 8.7 nM. In addition, R116010 is a selective inhibitor as indicated by its inhibition profile for several other cytochrome P450-mediated reactions. In T47D cell proliferation assays, R116010 by itself has no effect on cell proliferation. However, in combination with all-trans-retinoic acid, R116010 enhances the all-trans-retinoic acid-mediated antiproliferative activity in a concentration-dependent manner. In vivo, the growth of murine oestrogen-independent TA3-Ha mammary tumours is significantly inhibited by R116010 at doses as low as 0.16 mg kg(-1). In conclusion, R116010 is a highly potent and selective inhibitor of all-trans-retinoic acid metabolism, which is able to enhance the biological activity of all-trans-retinoic acid, thereby exhibiting antitumour activity. R116010 represents a novel and promising anticancer drug with an unique mechanism of action.
authors.affiliation: Department of Oncology Discovery Research, Johnson & Johnson Pharmaceutical Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Van Heusden
authors.forename: R
authors.initials: R
authors.lastname: Van Ginckel
authors.forename: H
authors.initials: H
authors.lastname: Bruwiere
authors.forename: P
authors.initials: P
authors.lastname: Moelans
authors.forename: B
authors.initials: B
authors.lastname: Janssen
authors.forename: W
authors.initials: W
authors.lastname: Floren
authors.forename: B J
authors.initials: BJ
authors.lastname: van der Leede
authors.forename: J
authors.initials: J
authors.lastname: van Dun
authors.forename: G
authors.initials: G
authors.lastname: Sanz
authors.forename: M
authors.initials: M
authors.lastname: Venet
authors.forename: L
authors.initials: L
authors.lastname: Dillen
authors.forename: C
authors.initials: C
authors.lastname: Van Hove
authors.forename: G
authors.initials: G
authors.lastname: Willemsens
authors.forename: M
authors.initials: M
authors.lastname: Janicot
authors.forename: W
authors.initials: W
authors.lastname: Wouters
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052160:Benzothiazoles; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; C450682:R116010; D013844:Thiazoles; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000072516:Retinoic Acid 4-Hydroxylase; C061121:liarozole