Restraining Cancer Cells by Dual‐Metabolic Inhibitions with a Mitochondrion‐Targeted Platinum(II) Complex

Cancer cells usually adapt metabolic phenotypes to chemotherapeutics. A defensive strategy against this flexibility is to modulate signaling pathways relevant to cancer bioenergetics. A triphenylphosphonium‐modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabolisms of cancer cells. TTP exhibits enhanced cytotoxicity against cisplatin‐insensitive human ovarian cancer cells in a caspase‐3‐independent way, and shows preferential inhibition on mitochondrial TrxR. The morphology and function of mitochondria are severely damaged, and the levels of mitochondrial and cellular reactive oxygen species are decreased. As a result, TTP exerts strong inhibition to both mitochondrial and glycolytic bioenergetics, inducing cancer cells to enter into a hypometabolic state.

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