Action Mechanism of Retinoid-Synergistic Dibenzodiazepines

Umemiya, Hiroki; Kagechika, Hiroyuki; Fukasawa, Hiroshi; Kawachi, Emiko; Ebisawa, Masayuki; Hashimoto, Yuichi; Eisenmann, Ghislaine; Erb, Cathie; Pornon, Astrid; Chambon, Pierre; Gronemeyer, Hinrich; Shudo, Koichi

doi:10.1006/bbrc.1997.6414

Cited by 35 publications

(27 citation statements)

References 31 publications

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“…This apparent contradiction may result from the ligand-binding property of LGD1069. Aa an RXR agonist LGD1069 binds with RXR ␣, ␤, ␥ and with high affinity (Ki values ϭ 3, 165, 98 nM respectively) and binds RAR ␣, ␤ and ␥ (Ki values ϭ 180, 50, 130 nM respectively) (13). We showed previously that the ligands of RAR inhibit adipose conversion reversibly.…”

Section: Discussionmentioning

confidence: 94%

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Synergistic Potentiation of Thiazolidinedione-Induced ST 13 Preadipocyte Differentiation by RAR Synergists

Sato

Yajima

Kawashima

et al. 2001

Biochemical and Biophysical Research Communications

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Section: Discussionmentioning

confidence: 94%

“…The affinities of HX600 and HX630 for the RXR receptor are 100-fold lower than LGD1069's but their synergistic effective concentration values (SEC 50 ) are the same as LGD1069 in HL-60 cell-differentiation systems (13). These results suggest that there might be some differences in action mode between LGD1069 and HX600 and HX630.…”

mentioning

confidence: 86%

Synergistic Potentiation of Thiazolidinedione-Induced ST 13 Preadipocyte Differentiation by RAR Synergists

Sato

Yajima

Kawashima

et al. 2001

Biochemical and Biophysical Research Communications

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“…Am 80, 16) an aromatic amide of retinoic acid, has been shown to bind to and activate RAR selectively. HX600, 17) a dibenzodiazepine derivative, has been shown to be a RXR selective agonist and also exhibits synergistic activity with RAR ligands, although HX600 itself can not activate RAR/RXR heterodimers. In this study, we did not succeed in finding a RXR-selective agonist among the 13-demethyl or 13-substituted analogues of ATRA and 9CRA.…”

Section: Discussionmentioning

confidence: 99%

Antitumoral Activity of 13-Demethyl or 13-Substituted Analogues of All-trans Retinoic Acid and 9-cis Retinoic Acid in the Human Myeloid Leukemia Cell Line HL-60

Mizuguchi

Wada

Nakagawa

et al. 2006

Biological & Pharmaceutical Bulletin

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The antitumoral activity of 13-demethyl or 13-substituted all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9CRA) was tested using the myeloid leukemia cell line HL-60. Cell proliferation, differentiation and apoptosis were evaluated by flow cytometry and DNA fragmentation assay. The ability to bind to human RXRa a and to activate either human retinoic acid response element (RARE)-mediated gene expression or rat CRABPII retinoid X response element (RXRa a)-mediated gene expression were determined using luciferase reporter plasmids. In terms of the magnitude of the regulatory activity for the proliferation and differentiation of HL-60 cells, the compounds ranked as follows: ATRAϾ13-ethyl ATRAϾ13-demethyl ATRAϾ13-phenylethyl ATRAϾ13-propyl ATRAϾ13-butyl ATRA (ATRA analogues) and 9CRAϾ13-ethyl 9CRAϾ13-demethyl 9CRAϾ13-propyl 9CRAϾ13-phenetyl 9CRAϾ13-butyl 9CRA (9CRA analogues). Regarding the magnitude of the apoptosis-inducing activity, the order was: 9CRAϾ13-ethyl 9CRAϾ13-demethyl 9CRA, with ATRA and its analogues and the other 9CRA analogues virtually inactive. Similar trends were observed in binding affinity for RXRa a and transactivation activity toward RARE-or RXRE-mediated gene expression. The results clearly indicate that the presence of a methyl group at C-13 is essential for the antitumoral activity of ATRA and 9CRA, and that bulky substituents exceeding two carbon atoms or the absence of substitution at position 13 significantly reduce the binding affinity for RAR and RXR, leading to a decreased RAR/RARE and/or RXR/RXRE-mediated gene expression.Key words all-trans retinoic acid (ATRA); 9-cis retinoic acid (9CRA); retinoic acid receptor (RAR); retinoic acid response element (RARE); retinoid X receptor (RXR); retinoid X response element (RXRE) buffered saline (PBS) [PBS(Ϫ)], the synchronization of the cell cycle was repeated in the same manner, and the cells thus obtained were used in the biological assays.Flow Cytometry Cells (10 5 cells/well) were placed in 24-well tissue culture plates and cultured for 3 d with retinoids (10 Ϫ10-10 Ϫ6 M) in RPMI-1640 medium at 37°C in a humidified atmosphere of 5% CO 2 in air. To reduce the effects of contact inhibition, control cells were adjusted to 60 to 70% confluency at the time of the FACS analysis. Each group of cells was collected in PBS(Ϫ). Then, the cells were resuspended in PBS(Ϫ) containing 0.2% Triton-X and 1 ml RNase, and incubated at 37°C for 1 h. Cells were washed with PBS(Ϫ) and incubated with 0.5 ml of DNA-staining solution containing propidium iodide (50 mg/ml) at 4°C for 20 min. The cells were analyzed with a flow cytometer equipped with an argon laser (488 nm, Becton Dickinson FACScan TM ) and the cell cycle distribution was analyzed using ModiFiT LT (Verity).Cell Surface Antigen Expression Analysis Cells (10 5 cells/well) were placed in 24-well tissue culture plates, and cultured for 3 d in RPMI-1640 medium with retinoids (10 Ϫ10-10 Ϫ6 M) under the same conditions as described for the flow cytometry. Each group of cells was then collected a...

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“…the sensitization of diabetic mice to insulin [24]and adipogenic differentiation of liposarcoma cells [25]. Likewise, retinoic acid or T3-induced differentiation of HL60 cells has been reported to be potentiated by RXR ligand through RXR heterodimer complexes, namely RXR:retinoic acid receptor and RXR:thyroid hormone receptor, respectively [26, 27]. …”

Section: Discussionmentioning

confidence: 99%

Thiazolidinedione Induces Apoptosis and Monocytic Differentiation in the Promyelocytic Leukemia Cell Line HL60

Hirase

Yanase

et al. 1999

Oncology

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Thiazolidinedione (TZD) is known to be a potent activator of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that constitutes a heterodimer with retinoid X receptor (RXR). Since a considerable amount of PPARγ is expressed in various hematopoietic cells, the present study was undertaken to examine the effect of TZD in the absence or presence of LG100268, an RXR-selective ligand, on a cultured promyelocytic leukemia cell line, HL60. Treatment with TZD (25–50 µM troglitazone or pioglitazone) markedly suppressed cell proliferation of HL60. A cell cycle analysis revealed that the suppressive effect of troglitazone on HL60 cell proliferations was caused by G0/G1 cell cycle arrest as well as by an apoptotic effect. Treatment with the same concentration of troglitazone also induced the monocytic differentiation of HL60 cells. The apoptotic or the differentiating effect of TZD on HL60 cells was synergistically enhanced by the combined treatment with 1 µM LG100268, while LG100268 alone neither had an apoptotic nor a differentiating effect on HL60 cells. These results suggest that these actions are mediated through the nuclear receptor system constituted by the PPARγ: RXR heterodimer.

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Action Mechanism of Retinoid-Synergistic Dibenzodiazepines

Cited by 35 publications

References 31 publications

Synergistic Potentiation of Thiazolidinedione-Induced ST 13 Preadipocyte Differentiation by RAR Synergists

Synergistic Potentiation of Thiazolidinedione-Induced ST 13 Preadipocyte Differentiation by RAR Synergists

Antitumoral Activity of 13-Demethyl or 13-Substituted Analogues of All-trans Retinoic Acid and 9-cis Retinoic Acid in the Human Myeloid Leukemia Cell Line HL-60

Thiazolidinedione Induces Apoptosis and Monocytic Differentiation in the Promyelocytic Leukemia Cell Line HL60

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