Endoplasmic Reticulum-Targeting Iridium(III) Complexes Induce Pyroptosis and Enhance Immunogenic Cell Death in MDA-MB-231 Cells

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-07-10 DOI:10.1021/acs.jmedchem.5c00883

Wei Wu, Jiaen Huang, Yuling Li, Jiaxi Chen, Xiaowei Kuang, Manzhen Ye, Rui Chen, Junli An, Zunnan Huang, Jing Sun

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引用次数: 0

Abstract

Cancer immunotherapy has revolutionized oncology by leveraging host immunity to eliminate malignant cells. In this study, five iridium(III) complexes (Ir1–Ir5) were synthesized and evaluated for their in vitro antitumor activity against various tumor cell lines. Among these, Ir4 and Ir5 exhibited the highest cytotoxicity and the most rapid cellular uptake in MDA-MB-231 cells. Colocalization experiments confirmed their accumulation in the endoplasmic reticulum (ER) and their ability to induce pyroptosis. Additionally, both complexes triggered ER stress, leading to increased calreticulin exposure on the cell surface, high-mobility group box 1 secretion, and ATP release, which collectively promoted immunogenic cell death. In vivo, a triple-dose Ir4 vaccine regimen significantly suppressed tumor growth compared to other treatment groups. These findings highlight the potential of Ir4-based novel triple-dose vaccination as a promising cancer immunotherapy strategy.

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内质网靶向铱（III）复合物诱导MDA-MB-231细胞焦亡并增强免疫原性细胞死亡

癌症免疫疗法通过利用宿主免疫来消除恶性细胞，彻底改变了肿瘤学。本研究合成了5种铱（III）配合物（Ir1-Ir5），并评价了它们对多种肿瘤细胞系的体外抗肿瘤活性。其中，Ir4和Ir5在MDA-MB-231细胞中表现出最高的细胞毒性和最快的细胞摄取。共定位实验证实了它们在内质网（ER）中的积累和诱导焦亡的能力。此外，这两种复合物都触发内质网应激，导致细胞表面钙调蛋白暴露增加，高迁移率的组盒1分泌和ATP释放，共同促进免疫原性细胞死亡。在体内，与其他治疗组相比，三剂量Ir4疫苗方案显著抑制肿瘤生长。这些发现突出了基于ir4的新型三剂量疫苗作为一种有前途的癌症免疫治疗策略的潜力。

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

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.