RESUMO
Three copper(II) complexes C1-C3 were synthesized and fully characterized as chemodynamic therapy (CDT) anticancer agents. C1-C3 showed greater cytotoxicity than their ligands toward SK-OV-3 and T24 cells. Particularly, C2 showed high cytotoxicity toward T24 cells and low cytotoxicity toward normal human HL-7702 and WI-38 cells. Mechanistic studies demonstrated that C2 oxidized GSH to GSSG and produced ËOH, which induced mitochondrial dysfunction and ER stress, finally leading to apoptosis of T24 cells. In addition, C2 inhibited autophagy by blocking autophagy flow, thereby closing the self-protection pathway of oxidative stress to enhance CDT. Importantly, C2 significantly inhibited T24 tumor growth with 57.1% inhibition in a mouse xenograft model. C2 is a promising lead as a potential CDT anticancer agent.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Cobre/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Estresse Oxidativo , Autofagia , Peróxido de Hidrogênio , Glutationa/metabolismoRESUMO
Twelve new complexes Cu(L1)2-Cu(L12)2 were designed and synthesized to improve their chemotherapeutic properties. They showed considerable antiproliferative activity against T24 cancer cells but lower cytotoxicity to human normal cells HL-7702 and WI-38. A mechanism study indicated that Cu(L4)2 and Cu(L10)2 were reduced to Fenton-like Cu+ by glutathione depletion, and the resulting Cu+ catalyzed the generation of highly toxic hydroxyl radicals from excess H2O2. Simultaneously, Cu(L4)2 and Cu(L10)2 could decrease the catalase activity to restrain H2O2 transfer to H2O for enhanced chemodynamic therapy (CDT). These induced mitochondrial dysfunctions and endoplasmic reticulum stress to induce T24 cell apoptosis. In addition, Cu(L4)2 and Cu(L10)2 inhibited autophagy flux to promote cell apoptosis. Cu(L4)2 and Cu(L10)2 demonstrated strong tumor inhibition ability in the T24 xenograft model. Moreover, Cu(L10)2 showed higher antitumor activity and a better safety profile than the CDT agent Cu1. Cu(L10)2 exhibited excellent pharmacokinetic properties. Collectively, Cu(L4)2 and Cu(L10)2 could be developed as potential CDT candidates for cancer treatment.