Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China.
Department of Radiation Oncology, Jiahui International Hospital, Shanghai, China.
Bioengineered. 2021 Dec;12(1):8679-8689. doi: 10.1080/21655979.2021.1991160.
Glioma is an intracranial malignant tumor with high morbidity in China. Limited efficacy has been achieved in the treatment of glioma through the application of epidermal growth factor receptor (EGFR) inhibitors, which is reported to be related to the poor permeability of the brain-blood barrier (BBB) to EGFR inhibitors. AZD3759 and osimertinib are both BBB-penetrating EGFR inhibitors. The present study aimed to investigate the inhibitory effects of AZD3759 and osimertinib on glioma and compare their efficacy and the underlying mechanisms. C6 and U87 cells were incubated with different concentrations of AZD3759 (1, 2, and 4 μM) and 4 μM osimertinib, respectively. C6-LUC xenograft animals were administered different doses of AZD3759 (15, 30, and 60 mg/kg) and 60 mg/kg osimertinib. We found that proliferation was significantly suppressed and that apoptosis and cell cycle arrest were dramatically induced in both C6 and U87 cells by AZD3759 in a dose-dependent manner. Compared to AZD3759, osimertinib had inferior effects on proliferation, apoptosis, and cell cycle. experiments verified that the anti-tumor efficacy of AZD3759 against C6 xenograft tumors was dose dependent and superior to that of osimertinib. The inhibitory effects of AZD3759 on the Janus kinase (JAK)/STAT pathway were observed in both glioma cells and tumor tissues, which were more significant than those of osimertinib. In conclusion, AZD3759 may inhibit the progression of glioma via a synergistic blockade of the EGFR and JAK/STAT signaling pathways.
脑胶质瘤是中国颅内的一种高发病率恶性肿瘤。通过应用表皮生长因子受体（EGFR）抑制剂治疗脑胶质瘤，疗效有限，据报道这与 EGFR 抑制剂对血脑屏障（BBB）的通透性差有关。AZD3759 和奥希替尼均为能穿透 BBB 的 EGFR 抑制剂。本研究旨在探讨 AZD3759 和奥希替尼对脑胶质瘤的抑制作用，并比较其疗效和潜在机制。将 C6 和 U87 细胞分别用不同浓度的 AZD3759（1、2 和 4 μM）和 4 μM 奥希替尼孵育。给 C6-LUC 异种移植动物给予不同剂量的 AZD3759（15、30 和 60 mg/kg）和 60 mg/kg 奥希替尼。结果发现，AZD3759 以剂量依赖性方式显著抑制 C6 和 U87 细胞的增殖，并显著诱导细胞凋亡和细胞周期停滞。与 AZD3759 相比，奥希替尼对增殖、凋亡和细胞周期的作用较弱。实验验证了 AZD3759 对 C6 异种移植肿瘤的抗肿瘤疗效呈剂量依赖性，优于奥希替尼。AZD3759 对 Janus 激酶（JAK）/STAT 通路的抑制作用在胶质瘤细胞和肿瘤组织中均观察到，其作用强于奥希替尼。综上所述，AZD3759 可能通过协同阻断 EGFR 和 JAK/STAT 信号通路抑制脑胶质瘤的进展。
