Dual Inhibition of Pyruvate Dehydrogenase Complex and Respiratory Chain Complex Induces Apoptosis by a Mitochondria‐Targeted Fluorescent Organic Arsenical in vitro and in vivo

Abstract Based on the potential therapeutic value in targeting mitochondria and the fluorophore tracing ability, a fluorescent mitochondria‐targeted organic arsenical PDT‐PAO‐F16 was fabricated, which not only visualized the cellular distribution, but also exerted anti‐cancer activity in vitro and in vivo via targeting pyruvate dehydrogenase complex (PDHC) and respiratory chain complexes in mitochondria. In details, PDT‐PAO‐F16 mainly accumulated into mitochondria within hours and suppressed the activity of PDHC resulting in the inhibition of ATP synthesis and thermogenesis disorder. Moreover, the suppression of respiratory chain complex I and IV accelerated the mitochondrial dysfunction leading to caspase family‐dependent apoptosis. In vivo, the acute promyelocytic leukemia was greatly alleviated in the PDT‐PAO‐F16 treated group in APL mice model. Our results demonstrated the organic arsenical precursor with fluorescence imaging and target‐anticancer efficacy is a promising anticancer drug.