Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas.
Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas.
复制标题
用于治疗皮肤T细胞淋巴瘤的链球烯类似物的发展。
作者：
贝沙罗汀是一种被批准用于治疗皮肤T细胞淋巴瘤（CTCL）的药物，由于其具有高度特异性的类维生素A X受体（RXR）激动剂的能力，被归类为rexinoid。类Rexinoids能够诱导RXR同源二聚化，从而诱导人癌症中的细胞凋亡和抑制增殖。许多研究表明，贝沙罗汀可有效降低CTCL细胞系的活力和增殖。然而，由于分别与视黄酸受体（RAR）、甲状腺激素受体（TR）和肝X受体（LXR）信号传导的交叉活性，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。在这项研究中，10种新的类似物和三种标准化合物与贝沙罗汀并排评估了它们驱动RXR同源二聚化和随后与RXR反应元件（RXRE）结合的能力。此外，还评估了这些类似物对CTCL细胞的增殖抑制、细胞毒性和致突变性。此外，通过qPCR分析最有效的类似物，以确定调节两种关键肿瘤抑制基因ATF 3和EGR 3表达的功效。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，因为它们显示增强的RXR激活，CTCL细胞增殖的减少相等或更大，以及诱导ATF 3和EGR 3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。RXR激动剂的修饰可以产生与母体化合物相比具有增强的生物选择性和效力的药剂，可能导致改善的患者结果。
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.
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影响因子：
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作者：
Budgin, JB;Richardson, SK;Rook, AH
通讯作者：
Rook, AH
影响因子：
7.3
作者：
Jurutka, Peter W.;Kaneko, Ichiro;Wagner, Carl E.
通讯作者：
Wagner, Carl E.
影响因子：
120.7
作者：
AXELROD, PI;LORBER, B;VONDERHEID, EC
通讯作者：
VONDERHEID, EC
影响因子：
4.6
作者：
Daina A;Michielin O;Zoete V
通讯作者：
Zoete V
DOI：
10.1128/cdli.6.1.79-84.1999
发表时间：
1999-01-01
期刊：
CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY
影响因子：
--
作者：
Lee, BN;Duvic, M;Reuben, JM
通讯作者：
Reuben, JM