Departamento de Química Inorgánica, Universidad de Murcia, and Murcia BioHealth Research Institute (IMIB-Arrixaca), 30071, Murcia, Spain.
Departamento de Bioquímica y Biología Molecular A. Unidad Docente de Biología, Facultad de Veterinaria, Universidad de Murcia, 30071, Murcia, Spain.
Cell Mol Life Sci. 2022 Sep 6;79(10):510. doi: 10.1007/s00018-022-04526-5.
Oncosis (from Greek ónkos, meaning "swelling") is a non-apoptotic cell death process related to energy depletion. In contrast to apoptosis, which is the main form of cell death induced by anticancer drugs, oncosis has been relatively less explored but holds potential to overcome drug resistance phenomena. In this study, we report a novel rationally designed mitochondria-targeted iridium(III) complex (OncoIr3) with advantageous properties as a bioimaging agent. OncoIr3 exhibited potent anticancer activity in vitro against cancer cells and displayed low toxicity to normal dividing cells. Flow cytometry and fluorescence-based assays confirmed an apoptosis-independent mechanism involving energy depletion, mitochondrial dysfunction and cellular swelling that matched with the oncotic process. Furthermore, a Caenorhabditis elegans tumoral model was developed to test this compound in vivo, which allowed us to prove a strong oncosis-derived antitumor activity in animals (with a 41% reduction of tumor area). Indeed, OncoIr3 was non-toxic to the nematodes and extended their mean lifespan by 18%. Altogether, these findings might shed new light on the development of anticancer metallodrugs with non-conventional modes of action such as oncosis, which could be of particular interest for the treatment of apoptosis-resistant cancers.
胀亡（来自希腊语 onkos，意为“肿胀”）是一种与能量耗竭相关的非细胞凋亡性细胞死亡过程。与作为抗癌药物诱导的主要细胞死亡形式的细胞凋亡不同，胀亡的研究相对较少，但有可能克服耐药现象。在这项研究中，我们报告了一种新型的合理设计的线粒体靶向铱(III)配合物（OncoIr3），具有作为生物成像剂的优势特性。OncoIr3 在体外对癌细胞表现出强大的抗癌活性，对正常分裂细胞的毒性较低。流式细胞术和荧光测定证实了一种凋亡非依赖性机制，涉及能量耗竭、线粒体功能障碍和细胞肿胀，与胀亡过程相匹配。此外，我们还开发了秀丽隐杆线虫肿瘤模型来体内测试该化合物，这使我们能够在动物中证明强烈的胀亡衍生的抗肿瘤活性（肿瘤面积减少 41%）。事实上，OncoIr3 对线虫无毒，并将它们的平均寿命延长了 18%。总的来说，这些发现可能为开发具有非传统作用模式的抗癌金属药物提供新的思路，如胀亡，这对于治疗凋亡抵抗的癌症可能特别有意义。
