The Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun 130022, PR China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
Nano Lett. 2021 Mar 24;21(6):2412-2421. doi: 10.1021/acs.nanolett.0c04402. Epub 2021 Mar 11.
JQ1, a specific inhibitor of bromodomain-containing protein 4 (BRD4), could have great potential in the treatment of cervical cancer. However, its clinical application is limited by its short plasma half-life and limited antitumor efficacy. In this work, cisplatin (CDDP) was first utilized as the stabilizer and cooperator in the nanosystem (mPEG--P(Glu--Phe)-CDDP/JQ1, called PGP-CDDP/JQ1) to break through the efficiency limitation of JQ1. The PGP-CDDP/JQ1 had a combination index (CI) of 0.21, exerting a strong cytotoxic synergistic effect. experiments revealed that PGP-CDDP/JQ1 had a significantly higher tumor inhibition effect (tumor inhibition rate: 85% vs 14%) and plasma stability of JQ1 (area under the curve (AUC): 335.97 vs 16.88 μg × h/mL) than free JQ1. The mechanism underling the synergism of JQ1 with CDDP in PGP-CDDP/JQ1 was uncovered to be inhibiting Plk1-mutant Trp53 axis. Thus, this study provides an optional method for improving the clinical application of JQ1 in cervical cancer.
JQ1 是一种特异性的溴结构域蛋白 4（BRD4）抑制剂，在宫颈癌的治疗中具有巨大的应用潜力。然而，其临床应用受到其血浆半衰期短和抗肿瘤疗效有限的限制。在这项工作中，顺铂（CDDP）首次被用作纳米系统（mPEG--P（Glu--Phe）-CDDP/JQ1，称为 PGP-CDDP/JQ1）中的稳定剂和协同剂，以突破 JQ1 的效率限制。PGP-CDDP/JQ1 的组合指数（CI）为 0.21，表现出强烈的细胞毒性协同作用。实验表明，PGP-CDDP/JQ1 具有更高的肿瘤抑制作用（肿瘤抑制率：85%比 14%）和 JQ1 的血浆稳定性（曲线下面积（AUC）：335.97 比 16.88μg×h/mL），优于游离 JQ1。PGP-CDDP/JQ1 中 JQ1 与 CDDP 协同作用的机制被揭示为抑制 Plk1 突变型 Trp53 轴。因此，本研究为提高 JQ1 在宫颈癌中的临床应用提供了一种可选方法。
