Potent anticancer activity of a novel iridium metallodrug via oncosis

Oncosis (from Greek onkos, 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. Oncolr3 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, Oncolr3 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 nonconventional modes of action such as oncosis, which could be of particular interest for the treatment of apoptosis-resistant cancers. [GRAPHICS] .

Automated summary

This study reports a novel mitochondria-targeted iridium(III) complex, OncoIr3, which exhibits advantageous properties as a bioimaging agent and shows potent anticancer activity in vitro and in vivo through an oncosis process.