Bexarotene

Bexarotene is a selective activator of retinoid X receptor (RXR), with EC₅₀ values of 0.028, 0.025, and 0.020µM for RXRα, RXRβ and RXRγ, respectively^[1]. Bexarotene can increase arylsulfatase A (ARSA) activity with an EC₅₀ value of 3.4μM^[2]. Bexarotene can be used as a model compound to develop a series of new derivatives and to evaluate the cytotoxicity of Bexarotene in glioma cells^[3].

In vitro, Bexarotene treatment for 48 hours showed an anti-proliferative effect with IC₅₀ values of 40.62±0.45µM for PC3 cells, and 50.20±4.10µM for DU145 cells^[4]. Treatment of ovarian cancer cells with 10µM Bexarotene for 24h significantly inhibited cell viability, reduced cell cyclin-related protein expression, and induced cell cycle arrest and pyroptosis^[5]. Bexarotene treatment (75μM; 24 hours) can reduce the levels of NF-κB and TAS in C6 cells, and increase the levels of PPARγ and 8-OHdG, stimulating oxidative stress in the cells^[6].

In vivo, Bezafibrate treatment via oral administration (0.3mg/kg/day) for 28 days alleviated the progression of motor dysfunction in the Parkinson's disease rat models, improved cognitive impairment, and reduced head twitching^[7]. Bexarotene treatment (100mg/kg/day; p.o.) for 30 days significantly reduced soluble β-amyloid and astrogliosis, accompanied by enhanced cognitive improvement in murine models of Alzheimer’s disease (AD)^[8].

References:
[1] Boehm M F, Zhang L, Zhi L, et al. Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells[J]. Journal of medicinal chemistry, 1995, 38(16): 3146-3155.
[2] Schlotawa L, Tyka K, Kettwig M, et al. Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency[J]. EMBO molecular medicine, 2023, 15(3): e14837.
[3] Gretskaya N M, Gamisonia A M, Dudina P V, et al. Novel bexarotene derivatives: Synthesis and cytotoxicity evaluation for glioma cells in 2D and 3D in vitro models[J]. European Journal of Pharmacology, 2020, 883: 173346.
[4] Shen D, Wang H, Zheng Q, et al. Synergistic effect of a retinoid X receptor-selective ligand bexarotene and docetaxel in prostate cancer[J]. OncoTargets and therapy, 2019: 7877-7886.
[5] Kobayashi T, Mitsuhashi A, Hongying P, et al. Bexarotene-induced cell death in ovarian cancer cells through Caspase-4-gasdermin E mediated pyroptosis[J]. Scientific reports, 2022, 12(1): 11123.
[6] Hacioglu C, Kar F, Kacar S, et al. Bexarotene inhibits cell proliferation by inducing oxidative stress, DNA damage and apoptosis via PPARγ/NF-κB signaling pathway in C6 glioma cells[J]. Medical Oncology, 2021, 38(3): 1-11.
[7] McFarland K, Spalding T A, Hubbard D, et al. Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson’s disease[J]. ACS chemical neuroscience, 2013, 4(11): 1430-1438.
[8] Muñoz-Cabrera J M, Sandoval-Hernández A G, Niño A, et al. Bexarotene therapy ameliorates behavioral deficits and induces functional and molecular changes in very-old Triple Transgenic Mice model of Alzheimer´ s disease[J]. PLoS One, 2019, 14(10): e0223578.

Bexarotene是一种选择性视黄醇X受体（RXR）激动剂，对RXRα、RXRβ和RXRγ的EC₅₀值分别为0.028µM、0.025µM和0.020µM^[1]。Bexarotene可增强芳基硫酸酯酶A（ARSA）活性（EC₅₀=3.4μM）[2]。Bexarotene可作为先导化合物用于开发新型衍生物及评估胶质瘤细胞毒性^[3]。

在体外，Bexarotene处理48小时对PC3和DU145细胞具有抗增殖作用，IC₅₀值分别为40.62±0.45µM和50.20±4.10µM^[4]。10µM的Bexarotene处理卵巢癌细胞24小时可显著抑制细胞活力、降低细胞周期蛋白相关表达，诱导细胞周期阻滞和细胞焦亡^[5]。75μM的Bexarotene处理C6细胞24小时能降低NF-κB和TAS水平，增加PPARγ和8-OHdG水平，激发细胞氧化应激^[6]。

在体内，帕金森病大鼠模型经口服Bexarotene（0.3mg/kg/day；持续28天）后，运动功能障碍进展得到缓解，认知障碍改善且头部抽搐减少^[7]。阿尔茨海默病（AD）小鼠模型经口服Bexarotene（100mg/kg/day；持续30天）后，可溶性β-淀粉样蛋白和星形胶质细胞增生显著减少，并伴随认知功能改善^[8]。