The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer.

IF 6 2区 医学 Q1 ONCOLOGY
Yehao Guo, Juyong Liang, Lingling Ding, Jiajun Wu, Weidong Teng, Jiafeng Wang, Liehao Jiang, Zhuo Tan
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引用次数: 0

Abstract

Background: Ferroptosis-induced therapy is a promising approach for treating anaplastic thyroid carcinoma (ATC), a highly lethal form of cancer. However, the specific effects of two anti-angiogenic agents, lenvatinib and anlotinib, on ferroptosis in ATC are not well understood.

Methods: Methods: To investigate the anticancer activity of lenvatinib and anlotinib in vivo, a subcutaneous tumor model was established in mice. The pharmacological effects of these agents on ATC cells were assessed using various assays, including CCK-8, colony formation, transwell, and sphere-forming assays. Angiogenesis was evaluated using a tubule formation assay. Reactive oxygen species (ROS) levels were measured by flow cytometry, and levels of ferroptosis and endoplasmic reticulum (ER) stress were determined through western blot assays. Immunohistochemistry analyses were used to profile the expression of GPX4, HO-1, PERK, and CHOP in tumor tissues.

Results: Both lenvatinib and anlotinib demonstrated dose- and time-dependent inhibition of Luciferase-8505 C-induced subcutaneous tumors in mice, with anlotinib showing greater efficacy than lenvatinib. In vitro experiments revealed that while both drugs were effective at inhibiting angiogenesis, anlotinib displayed superior antitumor effects in terms of cell viability, proliferation, tumor sphere formation, migration, and invasion. Mechanistic studies indicated that anlotinib induced ROS-mediated ferroptosis through the ER stress pathway, a response not observed with lenvatinib treatment.

Conclusion: Anlotinib showed superior efficacy in treating ATC compared to lenvatinib, independent of their anti-angiogenic properties. The ability of anlotinib to induce ER stress-mediated ferroptosis suggests that targeting ferroptosis may hold promise as a therapeutic strategy for ATC.

内质网应力-铁下垂相互信号调控了安洛替尼对间变性甲状腺癌的抗肿瘤作用。
背景:嗜铁诱导治疗是治疗间变性甲状腺癌(ATC)的一种很有前途的方法,ATC是一种高致死率的癌症。然而,两种抗血管生成药物lenvatinib和anlotinib对ATC中铁下垂的特异性作用尚不清楚。方法:建立小鼠皮下肿瘤模型,观察lenvatinib和anlotinib的体内抗癌活性。使用CCK-8、菌落形成、transwell和球体形成等多种方法评估这些药物对ATC细胞的药理作用。使用小管形成试验评估血管生成。流式细胞术检测活性氧(ROS)水平,western blot检测铁下垂和内质网(ER)应激水平。免疫组化分析GPX4、HO-1、PERK和CHOP在肿瘤组织中的表达。结果:lenvatinib和anlotinib对小鼠Luciferase-8505 c诱导的皮下肿瘤均表现出剂量依赖性和时间依赖性的抑制作用,且anlotinib的抑制作用优于lenvatinib。体外实验显示,虽然两种药物都能有效抑制血管生成,但安洛替尼在细胞活力、增殖、肿瘤球形成、迁移和侵袭方面表现出更强的抗肿瘤作用。机制研究表明,anlotinib通过内质网应激途径诱导ros介导的铁下垂,而lenvatinib治疗未观察到这一反应。结论:Anlotinib治疗ATC的疗效优于lenvatinib,与Anlotinib的抗血管生成特性无关。anlotinib诱导内质网应激介导的铁下垂的能力表明靶向铁下垂可能有望成为ATC的治疗策略。
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来源期刊
CiteScore
10.90
自引率
1.70%
发文量
360
审稿时长
1 months
期刊介绍: Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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