"目录号: HY-14652
Tamibarotene 是RARα/β激动剂，常用于癌症治疗。
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生物活性
Description
Tamibarotene is an agonist forretinoic acid receptor α/β, and used for cancer treatment.
In Vitro
Tamibarotene (20, 40 μM) down-regulates expression of cell cycle gene in T-cell lymphoma cells. Tamibarotene (5 μM) increases RARE activity in RARA-overexpressing cells to a much greater degree than in RARAlow cells. Moreover, RARAwt overexpression augments the degree of CDK2, CDK4, and CDK6 inhibition caused by Tamibarotene treatment[1]. Tamibarotene directly reverses the profibrotic phenotype of transforming growth factor-β1-treated dermal fibroblasts, suppresses ICAM-1 expression in endothelial cells, and promots M1 macrophage differentiation in vitro[2]. Tamibarotene (4 μM) up-regulates apelin mRNA and protein levels dose-dependently in VSMCs. Upon Tamibarotene stimulation, the RARα (retinoic acid receptor α) is recruited to the apelin promoter by interacting with KLF5 and Sp1 prebound to the TCE site of the apelin promoter to form a transcriptional activation complex, subsequently leading to the up-regulation of apelin expression in VSMCs. KLF5 and Sp1 co-operatively mediate Tamibarotene-induced apelin expression through their direct binding to the TCE on the apelin promoter[4].
In Vivo
Tamibarotene (1 mg/kg/day) significantly attenuates dermal and hypodermal fibrosis in bleomycin (BLM)-treated mice and tight skin 1 mice, respectively. Consistently, Tamibarotene significantly suppresses the expression of various molecules related to tissue fibrosis, including transforming growth factor-β1, connective tissue growth factor, IL-4, IL-10, IL-13, IL-17A, tumor necrosis factor-α, IFN-γ, and monocyte chemotactic protein 1 in the lesional skin of BLM-treated mice. Furthermore, Tamibarotene decreases the proportion of effector T cells, while increasing that of naive T cells among CD4+T cells in the draining lymph nodes of BLM-treated mice[2]. Tamibarotene (2.5 mg/kg, p.o.) does not result in any significant alteration of the AST, ALT, or ALP serum levels in periodontitis-challenged mice compared with that in untreated mice. Tamibarotene ameliorates alveolar bone resorption, significantly reduces the number ofP. gingivalis-induced osteoclasts in mice. Tamibarotene measurably increases the percentage of CD4+Foxp3+Treg cells as compared to those in EPD mice. Tamibarotene is also effective in reducing the expression of CD4+ROR-γt+(Th17) cells inP. gingivalis-infected gingival tissues and CLNs[3]. Tamibarotene (1 mg/kg, p.o.) increases apelin expression in balloon-injured arteries of rats, consistent with the results from the cultured VSMCs[4]. In aged SAMP8 mice, hippocampal ADAM10 levels improve after Tamibarotene (1 mg/kg/day) administration. Hes5 and Ki67 are restored and spatial working memory also improves after Tamibarotene administration[5].
Clinical Trial
CytRx
Acute Promyelocytic Leukemia
September 2007
Phase 2
CytRx
Stage IIIB Non-small Cell Lung Cancer With Pleural Effusion-Stage IV Non-small Cell Lung Cancer
April 2011
Phase 2
Northwestern University-CytRx-Cephalon
Acute Promyelocytic Leukemia
October 2009
Phase 1
St. Marianna University School of Medicine
HTLV-I-Associated Myelopathy
January 2011
Phase 2-Phase 3
Kinki University
Lupus Nephritis
September 2010
Phase 2
Osaka City University
Alzheimer's Disease
May 2010
Phase 2
R&R Inc.
Crohn's Disease
December 2006
Phase 2
Syros Pharmaceuticals
Acute Myeloid Leukemia-Myelodysplastic Syndrome
August 2016
Phase 2
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References
