Artemisinin derivatives differently affect cell death of lung cancer subtypes by regulating GPX4 in patient-derived tissue cultures.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-05-28 DOI:10.1038/s41420-025-02537-2

Johanna Mölleken, Angelique Kragl, Astrid Monecke, Isabella Metelmann, Sebastian Krämer, Sonja Kallendrusch

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引用次数: 0

Abstract

Resistant tumor cell populations are common after cytostatic drugs treatment. To overcome resistance mechanisms artemisinin derivatives, known for its complementary use during cancer treatement and ferroptosis induction, were investigated both as single agents and in combination with cisplatin (3 µM) in a complex organotypic tissue model of non-small cell lung cancer (NSCLC) patient samples. All substances-artemisinin (ART, 100 µM), artemether (ATM, 50 µM), artesunate (ATS, 20 µM), and dihydroartemisinin (DHA, 10 µM)-showed beneficial effects in most of the investigated patient-derived tissue cultures (PDTC). Tumor proliferation was reduced by DHA and ATS in both, standalone treatment and in combination with cisplatin, surpassing the efficacy of single cisplatin supplementation. In combination with cisplatin tumor apoptosis increased in most of lung squamous cell carcinoma (LUSC) PDTC, but not in lung adenocarcinoma (LUAD). The enzyme GPX4, inhibiting ferroptosis was up-regulated in LUAD but not in LUSC. Taken together, in the complex PDTC model system, LUSC displayed a higher sensitivity to ART derivatives, due to the lack of GPX4-mediated resistance to ferroptosis.

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在患者来源的组织培养中，青蒿素衍生物通过调节GPX4不同程度地影响肺癌亚型细胞死亡。

耐药肿瘤细胞群在细胞抑制剂治疗后很常见。为了克服耐药性机制，研究人员在非小细胞肺癌（NSCLC）患者样本的复杂器官型组织模型中，研究了青蒿素衍生物作为单一药物和与顺铂（3µM）联合使用的情况。所有物质——青蒿素（ART, 100µM）、蒿甲醚（ATM, 50µM）、青蒿琥酯（ATS, 20µM）和双氢青蒿素（DHA, 10µM）——在大多数研究的患者来源的组织培养（PDTC）中都显示出有益的作用。DHA和ATS在单独治疗和联合顺铂治疗两种情况下均能降低肿瘤增殖，超过单次补充顺铂的效果。在大多数肺鳞癌（LUSC）和肺腺癌（LUAD）中，顺铂联合使用可增加肿瘤细胞凋亡。抑制铁下垂的GPX4酶在LUAD中上调，而在LUSC中没有上调。综上所述，在复杂的PDTC模型系统中，由于缺乏gpx4介导的对铁下垂的抗性，LUSC对ART衍生物表现出更高的敏感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.