Capeloa Tania, Van de Velde Justine A, Pranzini Erica, Ippolito Luigi, Zampieri Luca X, Tardy Morgane, Vazeille Thibaut, Provito Alan, Carrà Giovanna, Scalera Alfonso, Payen Valéry L, Porporato Paolo E, Sonveaux Pierre
Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, 50134 Firenze, Italy.
iScience. 2025 Jun 28;28(8):113031. doi: 10.1016/j.isci.2025.113031. eCollection 2025 Aug 15.
For cancer patients, metastasis is a life-threatening event limiting therapeutic options. Molecularly, the metastatic phenotype can be conferred by mitochondrial reactive oxygen species (mtROS) generated upon metabolic stress. Mitochondrial damage can also trigger mtROS production, which is particularly well illustrated for anthracyclines. Here, we tested in mouse models of murine and human breast cancer whether this type of chemotherapy can trigger metastasis. We report that subcytotoxic doses of doxorubicin mimicking the clinical situation in poorly perfused tumor areas sequential trigger mtROS production, activate TGFβ pathway effector Pyk2, and increase cancer cell migration and invasion. Fortunately, the metastatic switch was incompletely induced, and doxorubicin did not promote breast cancer metastasis in immunocompetent mice. Yet, MitoTEMPO fully prevented metastatic dissemination and did not interfere with doxorubicin cytotoxicity, making it attractive to combine anthracyclines with mitochondria-targeted antioxidants.
对于癌症患者而言，转移是一种危及生命的事件，限制了治疗选择。从分子层面来看，代谢应激时产生的线粒体活性氧（mtROS）可赋予转移表型。线粒体损伤也能触发mtROS的产生，这在蒽环类药物的作用中表现得尤为明显。在此，我们在小鼠和人类乳腺癌的小鼠模型中测试了这类化疗是否会引发转移。我们报告称，模拟灌注不良肿瘤区域临床情况的亚细胞毒性剂量的阿霉素会依次触发mtROS的产生，激活TGFβ通路效应器Pyk2，并增加癌细胞的迁移和侵袭。幸运的是，转移开关并未被完全诱导，且阿霉素在具有免疫活性的小鼠中并未促进乳腺癌转移。然而，线粒体靶向抗氧化剂MitoTEMPO完全阻止了转移扩散，且不干扰阿霉素的细胞毒性，这使得将蒽环类药物与线粒体靶向抗氧化剂联合使用具有吸引力。
