RESUMO
The development and malignancy of cancer cells are closely related to the changes of the epigenome. In this work, a mitochondria-targeted rhenium(I) complex (DFX-Re3), integrating the clinical iron chelating agent deferasirox (DFX), has been designed. By relocating iron to the mitochondria and changing the key metabolic species related to epigenetic modifications, DFX-Re3 can elevate the methylation levels of histone, DNA, and RNA. As a consequence, DFX-Re3 affects the events related to apoptosis, RNA polymerases, and T-cell receptor signaling pathways. Finally, it is shown that DFX-Re3 induces immunogenic apoptotic cell death and exhibits potent antitumor activity in vivo. This study provides a new approach for the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.
Assuntos
Complexos de Coordenação/química , Ferro/metabolismo , Mitocôndrias/metabolismo , Rênio/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Deferasirox/química , Avaliação Pré-Clínica de Medicamentos , Epigenômica , Histonas/metabolismo , Humanos , Quelantes de Ferro/química , Metilação/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , RNA Polimerase II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
A TTPP probe was developed to distinguish G-quadruplexes (G4s) from other nucleic acid topologies through longer fluorescence lifetimes and higher quantum yields. In fluorescence lifetime imaging microscopy, TTPP enabled the visualization of cytoplasmic G4s in live cells, and showed the potential to detect cell apoptosis and ferroptosis by tracking cytoplasmic G4s.