Hydrolysis of 4-HPR to atRA occurs in vivo but is not required for retinamide-induced apoptosis.
The retinamide, N-(4-hydroxyphenyl)retinamide (4-HPR), has shown promising anti-tumor activity, but it is unclear whether this compound is hydrolyzed to all-trans retinoic acid (atRA) and if so, whether this plays any role in its chemotherapeutic activity. To address this issue, the ability of 4-hydroxybenzylretinone (4-HBR), a carbon-linked analog of 4-HPR, to support growth in vitamin A-deficient (VAD) animals and to activate an atRA-responsive gene in vivo was compared to 4-HPR and atRA. Further, the non-hydrolyzable 4-HBR analog was used to determine whether the presence of the labile amide linkage in 4-HPR is essential for the induction of apoptosis in cultured MCF-7 breast cancer cells. Studies in VAD rats showed that 4-HPR, like atRA, supports animal growth and induces CYP26B1 mRNA expression in lung whereas 4-HBR does not. Analysis of plasma from 4-HPR- and atRA-treated VAD animals revealed the presence of atRA whereas it was not detected in plasma from animals given 4-HBR. To determine whether hydrolysis to atRA is necessary for apoptosis induced by 4-HPR in MCF-7 breast cancer cells, morphological and biochemical assays for apoptosis were performed. 4-HBR, like 4-HPR, induced apoptosis in MCF-7 cells. Apoptosis was not induced even at high concentrations of atRA, showing that 4-HPR and 4-HBR act in cells via a distinct signaling pathway. These results show that although limited hydrolysis of 4-HPR occurs in vivo, the ability to liberate atRA is not required for these 4-hydroxyphenyl retinoids to induce apoptosis in MCF-7 breast cancer cells. Thus the non-hydrolyzable analog, 4-HBR, may have significant therapeutic advantage over 4-HPR because it does not liberate atRA that can contribute to the adverse side effects of drug administration in vivo.
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
Jason S
JS
Chapman
Kevin L
KL
Weiss
Robert W
RW
Curley
Margaret A
MA
Highland
Margaret
M
Clagett-Dame
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects* / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017313:Fenretinide / Q000008:administration & dosage*; D006801:Humans; D006868:Hydrolysis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014212:Tretinoin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood; D014801:Vitamin A / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D014802:Vitamin A Deficiency / Q000188:drug therapy / Q000503:physiopathology*
C451736:4-hydroxybenzylretinone; D014801:Vitamin A; D017313:Fenretinide; D014212:Tretinoin; C054441:retinamide