| Summary: | A series of seven novel iridium complexes were synthetized and characterized as potential photosensitizers for photodynamic therapy (PDT) applications. Among them, four complexes were evaluated in vitro for their anti-proliferative activity with and without irradiation on a panel of five cancer cell lines, namely PC-3 (prostate cancer), T24 (bladder cancer), MCF7 (breast cancer), A549 (lung cancer) and HeLa (cervix cancer), and two non-cancerous cell models (NIH-3T3 fibroblasts and MC3T3 osteoblasts). After irradiation at 458 nm, all tested complexes showed a strong selectivity against cancer cells, with a selectivity index (SI) ranging from 8 to 34 compared with non-cancerous cells. The cytotoxic effect of all these complexes was found to be independent of the anti-apoptotic protein Bcl-xL. The compound exhibiting the best selectivity, complex <b>4a</b>, was selected for further investigations. Complex <b>4a</b> was mainly localized in the mitochondria. We found that the loss of cell viability and the decrease in ATP and GSH content induced by complex <b>4a</b> were independent of both Bcl-xL and caspase activation, leading to a non-apoptotic cell death. By counteracting the intrinsic or acquired resistance to apoptosis associated with cancer, complex <b>4a</b> could be an interesting therapeutic alternative to be studied in preclinical models.
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