A novel quinoline and manganese‐based carbon monoxide‐releasing molecule for intravesical therapy of bladder cancer

Abstract Background and Purpose Bladder cancer remains a significant burden on public health globally. Carbon monoxide (CO) has emerged as a promising therapeutic agent for cancers because of its key role in inducing mitochondrial dysfunction and metabolic reprogramming in cancer cells; however, its clinical translation has been hindered by systemic toxicity because of its binding to haemoglobin, which is avoided by localised intravesical therapy via the bladder. This study aimed to develop and characterise a novel manganese(I)‐based CO releasing molecular MnCORM as a therapeutic agent against bladder cancer. Experimental Approach A new MnCORM chelate of a quinoline derivative was synthesised and characterised, and its anti‐cancer efficacy was assessed using a 2D bladder cancer cell model, a 3D tumour spheroid model, and a murine orthotopic bladder cancer model. Molecular mechanisms were explored via staining assays, transmission electron microscopy (TEM) and western blots. Key Results MnCORM inhibited cell viability and induced cell death in T24 and RT112 bladder cancer cells. MnCORM activated AMPK, whereas the AMPK inhibitor Compound C mitigated MnCORM‐induced cytotoxicity in T24 cancer cells. MnCORM induced AMPK‐triggered and Drp1‐dependent mitochondrial fission, promoted reactive oxygen species (ROS) accumulation, and induced mitophagy‐associated cell death. The inhibitory effect of MnCORM on tumour growth was validated in a 3D tumour spheroid model and further proven in an orthotopic bladder cancer model in nude mice after intravesical instillation of MnCORM (1 mg kg −1 ). Conclusions and Implications Our work shows that MnCORM could be potentially applied for bladder cancer therapy through intravesical instillation with less systemic toxicity.