RESUMO
Using copper-ionophores to translocate extracellular copper into mitochondria is a clinically validated anticancer strategy that has been identified as a new type of regulated cell death termed "cuproptosis." This study reports a mitochondria-targeting Cu(I) complex, Cu(I)Br(PPh3)3 (CBP), consisting of a cuprous ion coordinated by three triphenylphosphine moieties and a Br atom. CBP exhibited antitumor and antimetastatic efficacy in vitro and in vivo by specifically targeting mitochondria instigating mitochondrial dysfunction. The cytotoxicity of CBP could only be reversed by a copper chelator rather than inhibitors of the known cell death, indicating copper-dependent cytotoxicity. Furthermore, CBP induced the oligomerization of lipoylated proteins and the loss of Fe-S cluster proteins, consistent with characteristic features of cuproptosis. Additionally, CBP induced remarkable intracellular generation of reactive oxygen species (ROS) through a Fenton-like reaction, indicating a complex antitumor mechanism. This is a proof-of-concept study exploiting the antitumor activity and mechanism of the Cu(I)-based mitochondria-targeting therapy.
Assuntos
Antineoplásicos , Complexos de Coordenação , Cobre , Mitocôndrias , Espécies Reativas de Oxigênio , Cobre/química , Cobre/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Espécies Reativas de Oxigênio/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Camundongos , Linhagem Celular TumoralRESUMO
Herein, a giant Sb-rich polyoxometalate (POM) {Sb21 Tb7 W56 } is reported, which contains the largest number of Sb atoms in a POM so far. The Sb-rich POM has many interesting structural features and is a rare example of a soluble and water-stable giant POM. Biomedical studies indicate that the Sb-rich POM exhibits broad-spectrum antitumor activity against various cancer cell lines by reactivating the P53-dependent apoptotic processes and disrupting the mitochondrial membrane. In addition, this Sb-rich POM was capable of suppressing the growth and metastasis of a breast cancer in vivo. This work demonstrates that Sb-rich POMs are promising candidates for the development of new anticancer drugs.