Department of Pharmacology and Toxicology, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI, 48824, USA.
In Vivo Facility, Michigan State University, East Lansing, MI, USA.
Sci Rep. 2020 Dec 17;10(1):22244. doi: 10.1038/s41598-020-79260-8.
Effective drugs are needed for lung cancer, as this disease remains the leading cause of cancer-related deaths. Rexinoids are promising drug candidates for cancer therapy because of their ability to modulate genes involved in inflammation, cell proliferation or differentiation, and apoptosis through activation of the retinoid X receptor (RXR). The only currently FDA-approved rexinoid, bexarotene, is ineffective as a single agent for treating epithelial cancers and induces hypertriglyceridemia. Here, we used a previously validated screening paradigm to evaluate 23 novel rexinoids for biomarkers related to efficacy and safety. These biomarkers include suppression of inducible nitric oxide synthase (iNOS) and induction of sterol regulatory element-binding protein (SREBP). Because of its potent iNOS suppression, low SREBP induction, and activation of RXR, MSU-42011 was selected as our lead compound. We next used MSU-42011 to treat established tumors in a clinically relevant Kras-driven mouse model of lung cancer. KRAS is one of the most common driver mutations in human lung cancer and correlates with aggressive disease progression and poor patient prognosis. Ultrasound imaging was used to detect and monitor tumor development and growth over time in the lungs of the A/J mice. MSU-42011 markedly decreased the tumor number, size, and histopathology of lung tumors compared to the control and bexarotene groups. Histological sections of lung tumors in mice treated with MSU-42011 exhibited reduced cell density and fewer actively proliferating cells compared to the control and bexarotene-treated tumors. Although bexarotene significantly (p < 0.01) elevated plasma triglycerides and cholesterol, treatment with MSU-42011 did not increase these biomarkers, demonstrating a more favorable toxicity profile in vivo. The combination of MSU-42011 and carboplatin and paclitaxel reduced macrophages in the lung and increased activation markers of CD8+T cells compared to the control groups. Our results validate our screening paradigm for in vitro testing of novel rexinoids and demonstrate the potential for MSU-42011 to be developed for the treatment of KRAS-driven lung cancer.
需要有效的药物来治疗肺癌，因为这种疾病仍然是癌症相关死亡的主要原因。雷佐菌素类药物由于能够通过激活视黄醇 X 受体 (RXR) 来调节参与炎症、细胞增殖或分化以及细胞凋亡的基因，因此是很有前途的癌症治疗候选药物。唯一目前获得 FDA 批准的雷佐菌素类药物贝沙罗汀，作为单一药物治疗上皮癌无效，并导致高甘油三酯血症。在这里，我们使用了以前经过验证的筛选范式来评估 23 种新型雷佐菌素类药物与疗效和安全性相关的生物标志物。这些生物标志物包括抑制诱导型一氧化氮合酶 (iNOS) 和诱导固醇调节元件结合蛋白 (SREBP)。由于其强大的 iNOS 抑制作用、低 SREBP 诱导作用和 RXR 的激活，MSU-42011 被选为我们的先导化合物。接下来，我们使用 MSU-42011 治疗在临床上相关的 Kras 驱动的肺癌小鼠模型中已建立的肿瘤。KRAS 是人类肺癌中最常见的驱动突变之一，与侵袭性疾病进展和患者预后不良相关。超声成像用于检测和监测 A/J 小鼠肺部肿瘤随时间的发展和生长。与对照组和贝沙罗汀组相比，MSU-42011 显著减少了肿瘤数量、大小和肺肿瘤的组织病理学。与对照组和贝沙罗汀治疗的肿瘤相比，用 MSU-42011 治疗的小鼠肺肿瘤的组织学切片显示细胞密度降低，增殖活跃的细胞减少。尽管贝沙罗汀显著 (p < 0.01) 升高了血浆甘油三酯和胆固醇，但用 MSU-42011 治疗并未增加这些生物标志物，表明其体内毒性谱更有利。MSU-42011 与卡铂和紫杉醇联合使用可减少肺部的巨噬细胞，并增加 CD8+T 细胞的激活标志物，与对照组相比。我们的结果验证了我们用于新型雷佐菌素类药物体外测试的筛选范式，并证明了 MSU-42011 有潜力被开发用于治疗 KRAS 驱动的肺癌。
