文章：

小分子抑制剂BMS-754807通过抑制胰岛素样生长因子1受体/胰岛素受体信号通路改善实验性食管腺癌生存率

Inhibition of Insulin-like Growth Factor 1 Receptor/Insulin Receptor Signaling by Small-Molecule Inhibitor BMS-754807 Leads to Improved Survival in Experimental Esophageal Adenocarcinoma

原文发布日期：17 September 2024

DOI: 10.3390/cancers16183175

类型: Article

开放获取: 是

英文摘要：

The insulin-like growth factor-1 (IGF-1) and insulin axes are upregulated in obesity and obesity-associated esophageal adenocarcinoma (EAC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a contemporary nanotechnology-based paclitaxel (PT) bound to human albumin, ensuring its solubility in water rather than a toxic solvent. Here, we examined the benefits of inhibiting insulin-like growth factor-1 receptor/insulin receptor (IGF-1/IR) signaling and the enhancement of nab-paclitaxel effects by inclusion of the small-molecule inhibitor BMS-754807 using both in vitro and in vivo models of EAC. Using multiple EAC cell lines, BMS-754807 and nab-paclitaxel were evaluated as mono and combination therapies for in vitro effects on cell proliferation, cell death, and cell movement. We then analyzed the in vivo anticancer potency with survival improvement with BMS-754807 and nab-paclitaxel mono and combination therapies. BMS-754807 monotherapy suppressed in vitro cell proliferation and wound healing while increasing apoptosis. BMS-754807, when combined with nab-paclitaxel, enhanced those effects on the inhibition of cell proliferation, increment in cell apoptosis, and inhibition of wound healing. BMS-754807 with nab-paclitaxel produced substantially greater antitumor effects by increasing in vivo apoptosis, leading to increased mice survival compared to those of BMS-754807 or nab-paclitaxel monotherapy. Our outcomes support the use of BMS-754807, alone and in combination with nab-paclitaxel, as an efficient and innovative treatment choice for EAC.

摘要翻译： 

胰岛素样生长因子-1（IGF-1）与胰岛素轴在肥胖及肥胖相关食管腺癌（EAC）中呈现上调表达。纳米白蛋白结合型紫杉醇（nab-paclitaxel）是一种基于现代纳米技术、与人白蛋白结合的紫杉醇（PT）制剂，其通过白蛋白载体实现水溶性，避免了传统溶剂毒性。本研究通过体外与体内EAC模型，探讨了抑制胰岛素样生长因子-1受体/胰岛素受体（IGF-1/IR）信号通路的益处，以及联合小分子抑制剂BMS-754807对纳米白蛋白结合型紫杉醇疗效的增强作用。采用多种EAC细胞系，我们评估了BMS-754807与纳米白蛋白结合型紫杉醇单药及联合治疗对细胞增殖、细胞死亡及细胞迁移的体外影响。随后通过动物模型分析了BMS-754807与纳米白蛋白结合型紫杉醇单药及联合治疗的体内抗肿瘤效力及生存改善效果。BMS-754807单药治疗可抑制体外细胞增殖与伤口愈合能力，同时促进细胞凋亡。当BMS-754807与纳米白蛋白结合型紫杉醇联用时，对细胞增殖的抑制、细胞凋亡的促进以及伤口愈合的抑制作用均得到显著增强。相较于单药治疗，BMS-754807联合纳米白蛋白结合型紫杉醇通过显著提升体内细胞凋亡水平，产生更强的抗肿瘤效应，从而显著延长小鼠生存期。本研究结果支持BMS-754807单药及其与纳米白蛋白结合型紫杉醇联合方案作为EAC高效创新的治疗选择。

原文链接：

Inhibition of Insulin-like Growth Factor 1 Receptor/Insulin Receptor Signaling by Small-Molecule Inhibitor BMS-754807 Leads to Improved Survival in Experimental Esophageal Adenocarcinoma