Disease relevance of LG-629

• RARalpha antagonist Ro 41-5253 inhibits proliferation and induces apoptosis in breast-cancer cell lines [1].
• Such selective molecules may have a greater activity against lung cancer, with a more favourable toxicity profile, as recently suggested by our preliminary data on Ro 41-5253 [2].

High impact information on LG-629

• As demonstrated by gel retardation assays, Ro 41-5253 and two related new RAR alpha antagonists do not influence RAR alpha/RXR alpha heterodimerization and DNA binding [3].
• Remarkably, an RAR-alpha antagonist (Ro 41-5253) not only blocks the RAR-alpha-selective agonists but also the pan-reactive compounds [4].
• By using an RARalpha-selective antagonist (Ro 41-5253), we demonstrated that RARbeta expression was induced by atRA through an RARalpha-dependent signaling pathway and that RARbeta induction was correlated with IGFBP-3 induction [5].
• However, MCF-7 cells transfected with sense RARbeta cDNA expressed IGFBP-3 even in the presence of the RARalpha-selective antagonist Ro 41-5253 [5].
• MATERIALS AND METHODS: Limbs of chick embryos in ovo were implanted with retinoic pan-antagonist RO 41-5253-filled beads, and phenotypic changes were assessed by in situ hybridization [6].

Chemical compound and disease context of LG-629

• We analysed the anti-proliferative activity of two histone-deacetylase inhibitors (HDACIs), Trichostatin A (TSA) and sodium phenylbutyrate (PB), alone or combined with retinoids, all-trans retinoic acid (ATRA) and Ro 41-5253, on two human breast cancer cell lines: the hormone-dependent MCF-7 and the hormone-independent MDA-MB-231 [7].

Biological context of LG-629

• The RAR alpha-specific antagonist Ro 41-5253 had little effect on the down-regulation of EC-1 by retinoic acid [8].
• In the induction of apoptosis also ZR-75.1 cells are more sensitive to treatment with Ro 41-5253 than MCF-7 cells [1].
• Ro 41-5253 is a RARalpha-selective antagonist that binds RARalpha but does not induce transcriptional activation and does not influence RAR/RXR heterodimerization and DNA binding [1].
• Nonetheless, the RARalpha antagonist Ro 41-5253 did not block all the inhibitory effects of atRA, indicating that these inhibitory effects are not mediated by the RA response element (RARE) [9].
• CONCLUSION: Among the tested retinoids, RO 41-5253 exhibited marked effects on proliferation and RARs mRNA expression and its action appeared mainly related to a cell-cycle arrest rather than an apoptotic mechanism [10].

Anatomical context of LG-629

• Conversely, a RARalpha-selective antagonist, Ro 41-5253, suppressed the inhibitory ability of tRA on the XY gonad development [11].
• Ro 41-5253 reverted RA-induced inhibition of the differentiation of 3T3-L1 cells [12].

Associations of LG-629 with other chemical compounds

• Recently the synthetic retinoid Ro 41-5253 was identified as a selective RAR alpha antagonist [3].
• This effect was mimicked by a retinoic acid receptor alpha (RAR alpha) agonist (Ro 40-6055) and prevented by a specific antagonist (Ro 41-5253), indicating that it was mediated by RAR alpha [13].

Gene context of LG-629

• The RAR-alpha-selective antagonist Ro 41-5253, which inhibits RARE-dependent transcriptional activation, has by itself no effect on the differentiation of PCC4.aza1R cells [14].
• We previously reported that induction of MUC2, MUC5AC, and MUC5B gene expressions by retinoic acid is mediated by the retinoic acid receptor (RARalpha), and inhibited by the specific RARalpha antagonist Ro 41-5253 [15].
• All the tested retinoids appeared to activate the RAR-beta gene and major expression was evidenced following RO 44-4753 and RO 41-5253 treatment [10].
• RESULTS: We observed a marked antiproliferative rate with the RAR-gamma selective agonist RO 44-4753 and the RAR-alpha selective antagonist RO 41-5253; on the contrary, the other synthetic retinoids exhibited a rather low efficacy [10].
• Activation of RAR alpha contributed to K8 upregulation, since this effect was partially blocked by the RAR alpha-selective antagonist Ro-41-5253 [16].

Analytical, diagnostic and therapeutic context of LG-629

• The data obtained in this study represents the basis for a further evaluation of Ro 41-5253 anti-neoplastic activity on transgenic breast cancer animal models [17].

References