Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, 453000, Henan, P. R. China.
School of Basic Medical Science, Xinxiang Medical University, Xinxiang, 453000, Henan, P. R. China.
ChemMedChem. 2023 Aug 15;18(16):e202300131. doi: 10.1002/cmdc.202300131. Epub 2023 Jun 16.
Efficacy of clinical chemotherapeutic agents depends not only on direct cytostatic and cytotoxic effects but also involves in eliciting (re)activation of tumour immune effects. One way to provoke long-lasting antitumour immunity is coined as immunogenic cell death (ICD), exploiting the host immune system against tumour cells as a "second hit". Although metal-based antitumour complexes hold promise as potential chemotherapeutic agents, ruthenium (Ru)-based ICD inducers remain sparse. Herein, we report a half-sandwich complex Ru(II) bearing aryl-bis(imino) acenaphthene chelating ligand with ICD inducing properties for melanoma in vitro and in vivo. Complex Ru(II) displays strong anti-proliferative potency and potential cell migration inhibition against melanoma cell lines. Importantly, complex Ru(II) drives the multiple biochemical hallmarks of ICD in melanoma cells, i. e., the elevated expression of calreticulin (CRT), high mobility group box 1 (HMGB1), Hsp70 and secretion of ATP, followed by the decreased expression of phosphorylation of Stat3. In vivo the inhibition of tumour growth in prophylactic tumour vaccination model further confirms that mice with complex Ru(II)-treated dying cells lead to activate adaptive immune responses and anti-tumour immunity by the activation of ICD in melanoma cells. Mechanisms of action studies show that complex Ru(II)-induced ICD could be associated with mitochondrial damage, ER stress and impairment of metabolic status in melanoma cells. We believe that the half-sandwich complex Ru(II) as an ICD inducer in this work will help to design new half-sandwich Ru-based organometallic complexes with immunomodulatory response in melanoma treatments.
临床化学治疗剂的疗效不仅取决于直接的细胞抑制和细胞毒性作用,还涉及引发(重新)激活肿瘤免疫效应。一种引发持久抗肿瘤免疫的方法被称为免疫原性细胞死亡(ICD),利用宿主免疫系统对抗肿瘤细胞作为“第二次打击”。尽管基于金属的抗肿瘤配合物具有作为潜在化学治疗剂的潜力,但基于钌(Ru)的 ICD 诱导剂仍然很少。本文报道了一种半夹心配合物 Ru(II),其具有芳基双(亚氨基)吖啶螯合配体,具有体外和体内诱导黑色素瘤 ICD 的特性。配合物 Ru(II)对黑色素瘤细胞系表现出强烈的抗增殖活性和潜在的细胞迁移抑制作用。重要的是,配合物 Ru(II)驱动黑色素瘤细胞中 ICD 的多种生化特征,即钙网蛋白(CRT)、高迁移率族蛋白 1(HMGB1)、Hsp70 的高表达和 ATP 的分泌,随后磷酸化 Stat3 的表达降低。在预防性肿瘤疫苗接种模型中,体内肿瘤生长抑制进一步证实,用处理过的死亡细胞处理的小鼠通过激活 ICD 在黑色素瘤细胞中激活适应性免疫反应和抗肿瘤免疫。作用机制研究表明,配合物 Ru(II)诱导的 ICD 可能与黑色素瘤细胞中线粒体损伤、内质网应激和代谢状态受损有关。我们相信,本文中作为 ICD 诱导剂的半夹心配合物 Ru(II)将有助于设计具有免疫调节反应的新型基于半夹心 Ru 的有机金属配合物,用于黑色素瘤治疗。
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