El Hajj Diab Darine, Clerc Pascal, Serhan Nizar, Fourmy Daniel, Gigoux Véronique
INSERM ERL1226-Receptology and Therapeutic Targeting of Cancers, Laboratoire de Physique et Chimie des Nano-Objets, CNRS UMR5215-INSA, Université de Toulouse III, F-31432 Toulouse, France.
Nanomaterials (Basel). 2018 Jun 27;8(7):468. doi: 10.3390/nano8070468.
Doxorubicin is a cytotoxic drug used for the treatment of many cancer types. However, its significant dose-related adverse effects including cardiotoxicity may hamper its efficiency. Moreover, the multidrug resistance that appears during treatments limits anti-cancer therapies. Hyperthermia has been introduced as an adjuvant anti-cancer therapy and presents promising opportunities especially in combination with chemotherapy. However, hyperthermia methods including standard magnetic hyperthermia do not discriminate between the target and the surrounding normal tissues and can lead to side effects. In this context, a Magnetic Intra-Lysosomal Hyperthermia (MILH) approach, which occurs without perceptible temperature rise, has been developed. We previously showed that minute amounts of iron oxide magnetic nanoparticles targeting the gastrin receptor (CCK2R) are internalized by cancer cells through a CCK2R-dependent physiological process, accumulated into their lysosomes and kill cancer cells upon high frequency alternating magnetic field (AMF) application through lysosomal cell death. Here, we show that the combination of MILH with doxorubicin increases the efficiency of the eradication of endocrine tumor cells with synergism. We also demonstrate that these two treatments activate two different cell death pathways that are respectively dependent on Caspase-1 and Caspase-3 activation. These findings will result in the development of new anti-tumoral, intra-lysosomal-thermo/chemotherapy with better curative effects than chemotherapy alone and that are devoid of adverse effects linked to standard hyperthermia approaches.
阿霉素是一种用于治疗多种癌症类型的细胞毒性药物。然而，其与剂量相关的显著不良反应（包括心脏毒性）可能会妨碍其疗效。此外，治疗期间出现的多药耐药性限制了抗癌治疗。热疗已被引入作为一种辅助抗癌疗法，尤其在与化疗联合使用时展现出了广阔的前景。然而，包括标准磁热疗在内的热疗方法无法区分靶组织和周围正常组织，可能会导致副作用。在这种背景下，一种不会引起明显温度升高的磁内溶酶体热疗（MILH）方法被开发出来。我们之前表明，靶向胃泌素受体（CCK2R）的微量氧化铁磁性纳米颗粒通过CCK2R依赖的生理过程被癌细胞内化，积聚在它们的溶酶体中，并在施加高频交变磁场（AMF）时通过溶酶体细胞死亡杀死癌细胞。在此，我们表明MILH与阿霉素联合使用可协同提高内分泌肿瘤细胞的根除效率。我们还证明，这两种治疗激活了两条分别依赖于半胱天冬酶 -1和半胱天冬酶 -3激活的不同细胞死亡途径。这些发现将促成新的抗肿瘤内溶酶体热疗/化疗的开发，其疗效优于单纯化疗，且没有与标准热疗方法相关的不良反应。
