Mölleken Johanna, Kragl Angelique, Monecke Astrid, Metelmann Isabella, Krämer Sebastian, Kallendrusch Sonja
Institute of Anatomy, University of Leipzig, Leipzig, Germany.
Department of Thoracic Surgery, University Hospital Freiburg, Freiburg im Breisgau, Germany.
Cell Death Discov. 2025 May 28;11(1):256. doi: 10.1038/s41420-025-02537-2.
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.
在细胞抑制药物治疗后，耐药肿瘤细胞群体很常见。为了克服耐药机制，研究了青蒿素衍生物在非小细胞肺癌（NSCLC）患者样本的复杂器官型组织模型中作为单一药物以及与顺铂（3µM）联合使用的情况。青蒿素衍生物以其在癌症治疗和诱导铁死亡过程中的互补作用而闻名。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组织培养物（PDTC）中都显示出有益效果。在单独治疗以及与顺铂联合治疗中，DHA和ATS均降低了肿瘤增殖，其效果超过了单一补充顺铂的疗效。在与顺铂联合使用时，大多数肺鳞状细胞癌（LUSC）的PDTC中肿瘤细胞凋亡增加，但在肺腺癌（LUAD）中未增加。抑制铁死亡的酶GPX4在LUAD中上调，但在LUSC中未上调。综上所述，在复杂的PDTC模型系统中，由于缺乏GPX4介导的对铁死亡的抗性，LUSC对ART衍生物表现出更高的敏感性。
