PDF(Pubmed)
Abstract：
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.
摘要：
贝沙罗汀,一种被批准用于治疗皮肤T细胞淋巴瘤（CTCL）的药物，通过其作为具有高特异性的类视黄醇X受体(RXR)激动剂的能力而被分类为rexinoid。类Rexinoid能够诱导RXR同二聚化,导致诱导人癌症中的细胞凋亡和抑制增殖。大量研究表明，贝沙罗汀可有效降低CTCL细胞系的活力和增殖。然而,许多接受治疗的患者出现皮肤毒性，甲状腺功能减退,和高脂血症由于与视黄酸受体（RAR）的交叉活性，甲状腺激素受体（TR），和肝脏X受体（LXR）信号，分别。在这项研究中,将10种新的类似物和3种标准化合物与贝沙罗汀并列评价它们驱动RXR同二聚化和随后与RXR反应元件(RXRE)结合的能力。此外,评估这些类似物对CTCL细胞的增殖抑制作用，细胞毒性，和诱变性。此外，通过qPCR分析最有效的类似物，以确定调节两个关键肿瘤抑制基因表达的功效，ATF3和EGR3。我们的结果表明，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，在CTCL细胞增殖方面具有同等或更大的减少。以及诱导ATF3和EGR3的能力。这项工作拓宽了我们对RXR-配体关系的理解，并允许开发可能更有效的药物。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选择性和效力的药物。可能导致改善患者预后。
