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.