Simultaneous induction of apoptosis and ferroptosis by a novel thiolato-bridged manganese(I)-based CO-releasing molecule in pancreatic and prostate cancer cells.
Due to the invasive nature of cancer cells, therapies targeting a single cell death pathway alone often encounter drug resistance; therefore, the development of novel therapeutic strategies, such as the dual induction of apoptosis and ferroptosis, is warranted. This study investigated the anticancer mechanism of the newly synthesised thiolato-bridged manganese-based CO-releasing molecule (S-MnC) in highly metastatic pancreatic (PANC-1) and prostate (PC-3) cancer cells. The myoglobin assay showed controlled liberation of approximately 1.5 CO equivalents per S-MnC molecule in the dark, and approximately 1.1 equivalents under UV irradiation, consistent with a sustained single-donor profile. S-MnC induced apoptosis through ROS generation via Fenton-like reaction, mitochondrial membrane disruption, caspase activation, and DNA damage, culminating in G1-phase cell cycle arrest. Ferroptosis was triggered concurrently via p53-mediated suppression of SLC7A11 and GPX4, leading to GSH depletion, and iron overload was evident, with upregulated TFR1 expression. Notably, a crosstalk between these two cell death pathways was demonstrated, as ferrostatin pretreatment rescued the expression of apoptotic genes, suggesting that ferroptotic signalling actively contributes to the apoptotic response induced by S-MnC. Moreover, S-MnC also exhibited antimetastatic potential by suppressing MMP-2 and MMP-9. S-MnC showed promising binding potential towards pancreatic and prostate cancer-specific targets, mesothelin and prostate cancer-specific membrane antigen, with predicted binding energies of -8.4 and -9.1 kcal/mol, respectively. Our results, for the first time, establish that S-MnC is a potent, dual-action therapeutic agent that mediates both apoptosis and ferroptosis, offering a promising strategy to overcome drug resistance in aggressive, metastatic cancers and to enhance therapeutic efficacy.