Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
Arizona State University, School of Mathematical and Natural Sciences, Glendale, Arizona.
Cancer Prev Res (Phila). 2019 Apr;12(4):211-224. doi: 10.1158/1940-6207.CAPR-18-0317. Epub 2019 Feb 13.
Rexinoids, selective ligands for retinoid X receptors (RXR), have shown promise in preventing many types of cancer. However, the limited efficacy and undesirable lipidemic side-effects of the only clinically approved rexinoid, bexarotene, drive the search for new and better rexinoids. Here we report the evaluation of novel pyrimidinyl (Py) analogues of two known chemopreventive rexinoids, bexarotene (Bex) and LG100268 (LG268) in a new paradigm. We show that these novel derivatives were more effective agents than bexarotene for preventing lung carcinogenesis induced by a carcinogen. In addition, these new analogues have an improved safety profile. PyBex caused less elevation of plasma triglyceride levels than bexarotene, while PyLG268 reduced plasma cholesterol levels and hepatomegaly compared with LG100268. Notably, this new paradigm mechanistically emphasizes the immunomodulatory and anti-inflammatory activities of rexinoids. We reveal new immunomodulatory actions of the above rexinoids, especially their ability to diminish the percentage of macrophages and myeloid-derived suppressor cells in the lung and to redirect activation of M2 macrophages. The rexinoids also potently inhibit critical inflammatory mediators including IL6, IL1β, CCL9, and nitric oxide synthase (iNOS) induced by lipopolysaccharide. Moreover, iNOS and SREBP (sterol regulatory element-binding protein) induction assays correlate with efficacy and toxicity, respectively. Our results not only report novel pyrimidine derivatives of existing rexinoids, but also describe a series of biological screening assays that will guide the synthesis of additional rexinoids. Further progress in rexinoid synthesis, potency, and safety should eventually lead to a clinically acceptable and useful new drug for patients with cancer.
类视黄醇，视黄醇 X 受体（RXR）的选择性配体，在预防多种癌症方面显示出了希望。然而，唯一经临床批准的类视黄醇药物贝沙罗汀（bexarotene）的疗效有限且存在不良的血脂异常副作用，这促使人们寻找新的、更好的类视黄醇药物。在这里，我们报告了两种已知的化学预防类视黄醇药物——贝沙罗汀（Bex）和 LG100268（LG268）的新型嘧啶基（Py）类似物在新模型中的评估。我们表明，这些新型衍生物在预防致癌物诱导的肺癌发生方面比贝沙罗汀更有效。此外，这些新类似物具有改善的安全性特征。PyBex 引起的血浆甘油三酯水平升高低于贝沙罗汀，而 PyLG268 与 LG100268 相比降低了血浆胆固醇水平和肝肿大。值得注意的是，这种新模型从机制上强调了类视黄醇的免疫调节和抗炎活性。我们揭示了上述类视黄醇的新的免疫调节作用，特别是它们减少肺中巨噬细胞和髓源性抑制细胞的百分比以及重新定向 M2 巨噬细胞激活的能力。类视黄醇还能强烈抑制包括白细胞介素 6（IL6）、白细胞介素 1β（IL1β）、CCL9 和一氧化氮合酶（iNOS）在内的关键炎症介质的产生，这些介质由脂多糖诱导。此外，iNOS 和 SREBP（固醇调节元件结合蛋白）诱导测定分别与疗效和毒性相关。我们的研究结果不仅报告了现有的类视黄醇的新型嘧啶衍生物，还描述了一系列生物学筛选测定，这些测定将指导其他类视黄醇药物的合成。在类视黄醇合成、效力和安全性方面的进一步进展最终将为癌症患者带来一种临床可接受和有用的新药。
