Cuvelier Géraldine, Vermonden Perrine, Debisschop Pauline, Martin Manon, Derouane Françoise, Liebisch Gerhard, Ecker Josef, Hoering Marcus, Berlière Martine, Van Bockstal Mieke, Galant Christine, Duhoux François, Mourao Larissa, Scheele Colinda, Feron Olivier, Rezsohazy René, Corbet Cyril, Larondelle Yvan
Louvain Institute of Biomolecular Science and Technology, UCLouvain, 1348 Louvain-la-Neuve, Belgium.
Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, 1200 Brussels, Belgium.
Int J Mol Sci. 2025 Apr 4;26(7):3375. doi: 10.3390/ijms26073375.
Ferroptosis has recently emerged as a promising strategy to combat therapy-resistant cancers. As lipid peroxidation is a key trigger of ferroptotic cell death, enhancing cancer cell susceptibility through the supply of highly peroxidisable fatty acids represents a novel therapeutic approach. Conjugated linolenic acids (CLnAs) fulfill this requirement, exhibiting a peroxidation propagation rate eight times higher than their non-conjugated counterpart, α-linolenic acid. This study evaluates jacaric acid (JA), a plant-derived CLnA, as a ferroptotic inducer, both as a monotherapy and in combination with RAS-selective lethal 3 (RSL3), a canonical ferroptosis inducer, in 2D and 3D breast cancer cell models. JA treatment significantly reduced cell viability across all models, primarily through lipid peroxidation driven by JA incorporation into cellular lipids rather than alterations in anti-ferroptotic gene expression. Moreover, JA synergistically enhanced RSL3 cytotoxicity under 2D and several 3D conditions. Similar effects were observed with punicic acid, another plant-derived CLnA isomer. Our study exploits a common feature of cancer metabolism, increased fatty acid uptake, to turn it into a vulnerability. The incorporation of JA into breast cancer cells creates a highly peroxidisable environment that increases cancer cell sensitivity to RSL3, potentially reducing required doses and minimising side effects.
铁死亡最近已成为对抗难治性癌症的一种有前景的策略。由于脂质过氧化是铁死亡细胞死亡的关键触发因素，通过提供高度可过氧化的脂肪酸来增强癌细胞的易感性代表了一种新的治疗方法。共轭亚麻酸（CLnAs）满足这一要求，其过氧化传播速率比其非共轭对应物α-亚麻酸高八倍。本研究评估了源自植物的共轭亚麻酸紫铆酸（JA）作为铁死亡诱导剂的作用，在二维和三维乳腺癌细胞模型中，它既可以作为单一疗法，也可以与典型的铁死亡诱导剂RAS选择性致死3（RSL3）联合使用。JA处理在所有模型中均显著降低了细胞活力，主要是通过JA掺入细胞脂质驱动的脂质过氧化，而不是通过抗铁死亡基因表达的改变。此外，在二维和几种三维条件下，JA协同增强了RSL3的细胞毒性。另一种源自植物的共轭亚麻酸异构体石榴酸也观察到了类似的效果。我们的研究利用了癌症代谢的一个共同特征，即脂肪酸摄取增加，并将其转化为一个弱点。JA掺入乳腺癌细胞中会创造一个高度可过氧化的环境，从而增加癌细胞对RSL3的敏感性，有可能减少所需剂量并将副作用降至最低。
