Takayuki Hida*, Kenji Tai, Naoki Tokuhara, Akira Ishibashi, Kouichi Kikuchi,
Shigeki Hibi, Hiroyuki Yoshimura, Mitsuo Nagai, Toshihiko Yamauchi and Seiichi
Kobayashi
Tsukuba Research Laboratories for Drug Discovery, Eisai Co., Ltd., 5-1-3
Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
*Corresponding author. FAX: +81-298-47-2037
E-mail: t-hida@hhc.eisai.co.jp
Abstract: We previously reported that ER-27191 (4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)anthra[1,2-b]pyrrol-3-yl]benzoic
acid) is a potent antagonist of retinoicacid receptor (RAR), and ER-35795
((2E,4E,6E)-7-[1-(1-methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-2,4,6-nonatrienoic
acid) is a novel retinoid X receptor (RXR)-specific agonist. By usingthese
compounds, we investigated whether distinct RAR-dependent and RXR-dependent
pathways operate to mediate the diverse activities of retinoids, particularly,
the effects of the RXR pathway on cellular function. ER-27191 completely
antagonized HL60 cell differentiation induced by all-trans-retinoic
acid (atRA). However, the differentiation induced by the ER-35795 was not
antagonized at all by the RAR antagonist, but was inhibited by an RXR homodimer
antagonist (LGD100754, (2E,4E,6Z)-7-(3-n-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-3-methylocta-2,4,6-trienoic
acid). Its agonistic action on RXR/RAR heterodimer, on the other hand, was
neutralized by the RAR antagonist. During HL60 cell differentiation, atRA
induced RARb mRNA, while the RXR had no effect.
Interestingly, a functional RXR-pathway was also seen in lipopolysaccharide-induced
inhibition of mouse splenocyte proliferation. These results strongly suggest
the existence of a pharmacological RXR-dependent pathway that is activated
by a ligand that can bind to RXR.
Keywords: Retinoic acid receptor, Retinoid X receptor, ER-27191, ER-35795,
HL60 differentiation
Copyright The Japanese Pharmacological Society
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