School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA.
College of Medicine, University of Arizona, Phoenix, AZ 85004, USA.
Cells. 2023 Nov 4;12(21):2575. doi: 10.3390/cells12212575.
Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, 10 novel analogs and three standard compounds were evaluated side-by-side with bexarotene for their ability to drive RXR homodimerization and subsequent binding to the RXR response element (RXRE). In addition, these analogs were assessed for proliferation inhibition of CTCL cells, cytotoxicity, and mutagenicity. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds may possess similar or enhanced therapeutic potential since they display enhanced RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR-ligand relationships and permits development of possibly more efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes.
倍他罗汀是一种已被批准用于治疗皮肤 T 细胞淋巴瘤（CTCL）的药物，因其作为视黄醇 X 受体（RXR）激动剂的高特异性而被归类为维甲酸受体（RXR）激动剂。维甲酸受体能够诱导 RXR 同源二聚体形成，从而导致人类癌症中的细胞凋亡和增殖抑制。许多研究表明，倍他罗汀可有效降低 CTCL 细胞系的活力和增殖。然而，由于与视黄酸受体（RAR）、甲状腺激素受体（TR）和肝 X 受体（LXR）信号通路的交叉活性，许多接受治疗的患者会出现皮肤毒性、甲状腺功能减退症和高脂血症。在这项研究中，10 种新型类似物和 3 种标准化合物与倍他罗汀一起进行了评估，以评估它们驱动 RXR 同源二聚体形成和随后与 RXR 反应元件（RXRE）结合的能力。此外，还评估了这些类似物对 CTCL 细胞增殖抑制、细胞毒性和致突变性的作用。此外，通过 qPCR 分析了最有效的类似物，以确定它们在调节两个关键肿瘤抑制基因 ATF3 和 EGR3 的表达方面的功效。我们的研究结果表明，这些新化合物可能具有相似或增强的治疗潜力，因为它们显示出增强的 RXR 激活作用，同时等效或更大程度地降低了 CTCL 细胞的增殖，并且能够诱导 ATF3 和 EGR3。这项工作拓宽了我们对 RXR 配体关系的理解，并允许开发出可能更有效的药物。与母体化合物相比，RXR 激动剂的修饰可以产生具有增强的生物学选择性和效力的药物，从而可能改善患者的治疗效果。
