A new class of retinoids with selective inhibition of AP-1 inhibits proliferation.
Retinoids regulate many biological processes, including differentiation, morphogenesis and cell proliferation. They are also important therapeutic agents, but their clinical usefulness is limited because of side effects. Retinoid activities are mediated by specific nuclear receptors, the RARs and RXRs, which can induce transcriptional activation through specific DNA sites or by inhibiting the transcription factor AP-1 (refs 12-15), which usually mediates cell proliferation signals. Because the two types of receptor actions are mechanistically distinct, we investigated whether conformationally restricted retinoids, selective for each type of receptor action, could be identified. Here we describe a new class of retinoids that selectively inhibits AP-1 activity but does not activate transcription. These retinoids do not induce differentiation in F9 cells but inhibit effectively the proliferation of several tumour cell lines, and could thus serve as candidates for new retinoid therapeutic agents with reduced side effects.
Cancer Center, La Jolla Cancer Research Foundation, La Jolla, California 92037.
A
A
Fanjul
M I
MI
Dawson
P D
PD
Hobbs
L
L
Jong
J F
JF
Cameron
E
E
Harlev
G
G
Graupner
X P
XP
Lu
M
M
Pfahl
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008968:Molecular Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000187:drug effects; D047488:Retinoid X Receptors; D012176:Retinoids / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D018808:Transcription Factor AP-1; D014157:Transcription Factors