A polo-like kinase 1 inhibitor enhances erastin sensitivity in head and neck squamous cell carcinoma cells in vitro.

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-08-01 Epub Date: 2024-03-27 DOI:10.1007/s00280-024-04654-8
Xiangping Wu, Jing Wu
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Abstract

Background: Polo-like kinase 1 (PLK1) is a critical therapeutic target in the treatment of head and neck squamous cell carcinoma (HNSCC). The objective of this study was to investigate the therapeutic effect of the combination of BI 2536, a PLK1 inhibitor, and erastin, a ferroptosis inducer, in HNSCC.

Methods: The proliferation, invasion, and migration abilities of Tu177 and FaDu cells upon exposure to BI 2536 and erastin, used in combination or alone, were tested. Fe2+, glutathione (GSH), and malondialdehyde (MDA) detection kits were used to determine whether the addition of BI 2536 enhanced the accumulation of Fe2+ and MDA, along with the depletion of GSH. Quantitative real-time PCR, western blot analyses were performed to investigate whether BI 2536 further altered the mRNA and expression level of ferroptosis genes. Furthermore, si PLK1 was used to investigate whether targeting PLK1 gene promoted erastin-induced ferroptosis.

Results: The combination of BI 2536 and erastin exerted a stronger cytotoxicity than treatment with a single agent. Compared with erastin treatment alone, the combination of BI 2536 and erastin lowered the ability of tumor cells to self-clone, invade, and migrate. BI 2536 enhanced the accumulation of Fe2+ and MDA, and the depletion of GSH. BI 2536 increased erastin-induced changes in ferroptosis-related gene mRNA and expression. Importantly, targeting PKL1 enhanced the anti-cancer effect of erastin.

Conclusion: BI 2536 enhanced the sensitivity of HNSCC cells to erastin, which provides a new perspective for cancer treatment.

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一种多聚样激酶 1 抑制剂在体外增强了头颈部鳞状细胞癌细胞对厄拉斯汀的敏感性。
背景:Polo-like激酶1(PLK1)是治疗头颈部鳞状细胞癌(HNSCC)的关键治疗靶点。本研究的目的是探讨 PLK1 抑制剂 BI 2536 和铁变态反应诱导剂厄拉斯汀联合应用对 HNSCC 的治疗效果:方法:测试了Tu177和FaDu细胞在联合或单独使用BI 2536和厄拉斯汀后的增殖、侵袭和迁移能力。使用 Fe2+、谷胱甘肽(GSH)和丙二醛(MDA)检测试剂盒确定 BI 2536 的添加是否会增强 Fe2+ 和 MDA 的积累以及 GSH 的消耗。为了研究 BI 2536 是否进一步改变了铁突变基因的 mRNA 和表达水平,还进行了定量实时 PCR 和 Western 印迹分析。此外,还使用了 si PLK1 来研究靶向 PLK1 基因是否促进了麦拉宁诱导的铁变态反应:结果:BI 2536和厄拉斯汀联合用药比单药治疗具有更强的细胞毒性。与单用厄拉斯汀治疗相比,BI 2536 和厄拉斯汀联合用药可降低肿瘤细胞的自我克隆、侵袭和迁移能力。BI 2536能增强Fe2+和MDA的积累以及GSH的消耗。BI 2536 增加了厄拉斯汀诱导的铁突变相关基因 mRNA 和表达的变化。重要的是,以PKL1为靶点增强了厄拉斯汀的抗癌效果:BI 2536增强了HNSCC细胞对厄拉斯汀的敏感性,为癌症治疗提供了新的视角。
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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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