Retinoids in neuroblastoma therapy: distinct biological properties of 9-cis- and all-trans-retinoic acid.
We investigated the potential for 9-cis-retinoic acid in the differentiation therapy of neuroblastoma using an N-type neuroblastoma cell line, SH SY 5Y, as an experimental model. In these cells, 9-cis-retinoic acid is more effective than other isomers at inducing the expression of RAR-beta. An RAR-alpha-specific antagonist inhibited the induction of RAR-beta in response to all-trans-but not to 9-cis-retinoic acid. This indicates that the mechanism of gene induction by 9-cis-retinoic acid differs markedly from all-trans-retinoic acid. 9-cis-retinoic acid is also better than all-trans at producing sustained morphological differentiation and inhibition of proliferation of SH SY 5Y cells. Although N-type neuroblastoma cells are not thought to undergo apoptosis in response to all-trans-retinoic acid, we observed a significant degree of apoptosis in SH SY 5Y cells treated with 9-cis-retinoic acid for 5 days and then cultured in the absence of retinoid, an effect not observed in cells treated with the all-trans isomer. These results suggest that 9-cis- and all-trans-retinoic acid have distinct biological properties and that 9-cis retinoic acid may be clinically effective in neuroblastoma by inducing both differentiation and apoptosis under an appropriate treatment regimen.
Lovat
P E
PE
Department of Medicine, University of Newcastle upon Tyne, U.K.
Irving
H
H
Annicchiarico-Petruzzelli
M
M
Bernassola
F
F
Malcolm
A J
AJ
Pearson
A D
AD
Melino
G
G
Redfern
C P
CP
D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D001565:Benzoates; D002839:Chromans; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C082925:retinoic acid receptor beta; C084904:Ro 41-5253; D000077556:Alitretinoin; D014212:Tretinoin