Donati Chiara, Hashim Ishfaq Ibni, Pozsoni Nestor Bracho, Bourda Laurens, Van Hecke Kristof, Cazin Catherine S J, Visentin Fabiano, Nolan Steven P, Gandin Valentina, Scattolin Thomas
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova via Marzolo 5 35131 Padova Italy
Department of Chemistry and Centre for Sustainable Chemistry, Ghent University Krijgslaan 281,S-3 9000 Ghent Belgium
RSC Med Chem. 2025 Mar 19. doi: 10.1039/d5md00039d.
Immunogenic cell death (ICD) is a regulated form of cell death that activates an immune response through the release of danger-associated molecular patterns (DAMPs), including calreticulin, ATP, and HMGB1. Gold complexes are known to induce ICD, but the ICD-inducing potential of palladium complexes remains largely unexplored. We report the first examples of palladium compounds capable of inducing ICD, specifically allyl palladates bearing bis(imino)acenaphthene-NHC (BIAN-NHC) ligands. Cytotoxicity tests on human cancer cell lines revealed that allyl palladates outperform their cinnamyl analogues and gold(i)/copper(i) BIAN-NHC complexes. Notably, [BIAN-IMes·H][PdCl(allyl)] 2a showed excellent TrxR inhibition, reducing activity by 67% and surpassing auranofin. This inhibition strongly correlates with ICD induction, as evidenced by enhanced DAMP marker expression, including superior ATP and HMGB1 release compared to doxorubicin. These findings establish allyl palladates as a novel class of ICD inducers with dual anticancer activity and immune activation potential.
免疫原性细胞死亡（ICD）是一种受调控的细胞死亡形式，它通过释放包括钙网蛋白、三磷酸腺苷（ATP）和高迁移率族蛋白B1（HMGB1）在内的危险相关分子模式（DAMPs）来激活免疫反应。已知金配合物可诱导ICD，但钯配合物诱导ICD的潜力在很大程度上仍未得到探索。我们报道了首例能够诱导ICD的钯化合物，具体为带有双（亚氨基）苊-N-杂环卡宾（BIAN-NHC）配体的烯丙基钯酸酯。对人类癌细胞系的细胞毒性测试表明，烯丙基钯酸酯的表现优于其肉桂基类似物以及金（I）/铜（I）BIAN-NHC配合物。值得注意的是，[BIAN-IMes·H][PdCl(allyl)] 2a表现出出色的硫氧还蛋白还原酶（TrxR）抑制作用，活性降低了67%，超过了金诺芬。这种抑制作用与ICD诱导密切相关，与阿霉素相比，DAMP标志物表达增强，包括ATP和HMGB1释放增加，证明了这一点。这些发现确立了烯丙基钯酸酯作为一类具有双重抗癌活性和免疫激活潜力的新型ICD诱导剂。
