Photodynamic therapy
(PDT) for cancer treatment has drawn increased
attention over the last decades. Herein, we introduce a novel family
of low-molecular-weight coumarins as potential PDT anticancer tools.
Through a systematic study with a library of 15 compounds, we have
established a detailed structure–activity relationship rationale,
which allowed the selection of three lead compounds exhibiting effective
in vitro anticancer activities upon visible-light irradiation in both
normoxia and hypoxia (phototherapeutic indexes up to 71) and minimal
toxicity toward normal cells. Acting as excellent theranostic agents
targeting mitochondria, the mechanism of action of the photosensitizers
has been investigated in detail in HeLa cells. The generation of cytotoxic
reactive oxygen species, which has been found to be a major contributor
of the coumarins’ phototoxicity, and the induction of apoptosis
and/or autophagy have been identified as the cell death modes triggered
after irradiation with low doses of visible light.
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.
Graphical abstract
New Ru(ii) arene anticancer complexes with a non-coordinated CHO group that are able to inhibit the protein synthesis; this is a new mode of action for half-sandwich metal complexes.
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