Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China.
Medical Center, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), No.19, Xinhua Road, Xiuying Distric, Haikou, 570311, Hainan Province, China.
Cancer Chemother Pharmacol. 2020 May;85(5):949-957. doi: 10.1007/s00280-020-04068-2. Epub 2020 Apr 11.
The poor outcomes in nasopharyngeal carcinoma (NPC) necessitate new treatments. AT7519 is a potent inhibitor of several cyclin-dependent kinases (CDKs) and is currently in the early phase of clinical development for cancer treatment. The potent anti-cancer activities of AT7519 have been reported in various cancers, but not in NPC.
The effects of AT7519 in NPC were systematically analyzed using cell culture assays and xenograft mouse models. The effects of AT7519 on molecules involved in mRNA transcription were examined.
AT7519, at a nanomolar concentration, significantly inhibits growth via arresting cells at G2/M phase, and induces apoptosis in NPC cells regardless of Epstein-Barr virus (EBV) infection and cellular origin. It also inhibits growth of a subpopulation of cells with highly proliferative and invasive features. Importantly, AT7519 acts synergistically with cisplatin and is effective against chemo-resistant NPC cells. Mechanistically, AT7519 inhibits phosphorylation of Rb, suggesting the inhibition of CDK2 in NPC. It also decreases N-myc level and RNA polymerase II phosphorylation, and inhibits transcription. Consistent with the in vitro findings, we demonstrate that AT7519 is effective as a single agent in two independent NPC xenograft mouse models. The combination of ATP7519 and cisplatin results in greater efficacy than cisplatin alone in inhibiting NPC tumor growth.
Our work is the first to report anti-NPC activities of AT7519. Our preclinical evidence suggests that AT7519 is a useful addition to overcome NPC chemo-resistance.
鼻咽癌（NPC）的预后较差，需要新的治疗方法。AT7519 是几种细胞周期蛋白依赖性激酶（CDKs）的有效抑制剂，目前正处于癌症治疗的早期临床开发阶段。AT7519 在各种癌症中的抗肿瘤活性已被报道，但在 NPC 中尚未见报道。
使用细胞培养实验和异种移植小鼠模型系统地分析了 AT7519 在 NPC 中的作用。研究了 AT7519 对参与 mRNA 转录的分子的影响。
AT7519 在纳摩尔浓度下通过将细胞阻滞在 G2/M 期显著抑制生长，并诱导 NPC 细胞凋亡，无论 EBV 感染和细胞起源如何。它还抑制具有高增殖和侵袭特征的亚群细胞的生长。重要的是，AT7519 与顺铂协同作用，对化疗耐药的 NPC 细胞有效。机制上，AT7519 抑制 Rb 的磷酸化，提示其在 NPC 中抑制 CDK2。它还降低 N-myc 水平和 RNA 聚合酶 II 的磷酸化，并抑制转录。与体外研究结果一致，我们证明 AT7519 在两种独立的 NPC 异种移植小鼠模型中作为单一药物有效。AT7519 与顺铂联合使用比单独使用顺铂更能抑制 NPC 肿瘤生长。
我们的工作首次报道了 AT7519 对 NPC 的抗肿瘤活性。我们的临床前证据表明，AT7519 是克服 NPC 化疗耐药性的有用方法。
