RESUMO
PDT is a well-established therapeutic modality for many types of cancer. Photoluminescent cyclometalated iridium(III) complexes are one of the most commonly used classes of organometallic compounds with potential beneficial applications in bioimaging and as promising anticancer agents. In the present study, three new cyclometalated iridium(III) complexes (Ir1-Ir3) containing guanidinium ligands were found to exert excellent cytotoxic effects on different types of cancer cells upon light irradiation at 425â¯nm. Notably, Ir1 conferred almost no dark toxicity (IC50â¯>â¯100⯵M) to HepG2 cells, but the value decreased by 387-fold to 0.36⯵M following 10â¯min of light irradiation (425â¯nm). Further mechanistic investigation revealed that complex Ir1 could induce apoptosis via the activation of reactive oxygen species (ROS)-mediated mitochondrial signaling pathways in the presence or absence of light irradiation. In vivo studies demonstrated that Ir1 significantly inhibited tumor growth in HepG2 xenograft-bearing mice under light irradiation at 425â¯nm. Taken together, these findings indicate that designing PDT-based Ir(III) complexes may hold a great deal of promise for anticancer drug development.
Assuntos
Antineoplásicos/farmacologia , Guanidina/farmacologia , Irídio/farmacologia , Mitocôndrias/efeitos dos fármacos , Imagem Óptica , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Guanidina/química , Células Hep G2 , Humanos , Irídio/química , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Mitocôndrias/patologia , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-AtividadeRESUMO
DESCRIPTION: Two new ruthenium(II) complexes containing guanidinium as ligands, [Ru(dip)2 (L1)]3+ (Ru1) and [Ru(dip)2(L2)]3+ (Ru2) (dip=4,7-diphenyl-1,10-phenanthroline; L1=1-(4-(1H-imidazo[4,5- f][1,10]phenanthrolin-2-yl)phenyl)guanidine cation; L2 = 1-(3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl) phenyl)guanidine cation) have been synthesized and characterized. Both complexes display higher cytotoxicity against several cancer cell lines compared to cisplatin and are less cytotoxic on the nontumorigenic cell line LO2. Intracellular distribution studies show that these complexes are selectively localized in the cytoplasm. FINDINGS: Further analysis revealed that Ru1 and Ru2 had no obvious effects on the cell cycle and induced apoptosis in HeLa cells via the mitochondrial pathway, which involved reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and Bcl-2 family member activation. Taken together, the two complexes have the potential to be utilized as anticancer agents.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Guanidina/farmacologia , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Guanidina/química , Humanos , Ligantes , Estrutura Molecular , Rutênio/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Guanidinium-functionalized molecules are commonly studied for their use as pharmaceutically active compounds and drugs carriers. Herein, four cyclometalated iridium(III) complexes containing guanidinium ligands have been synthesized and characterized as potential anticancer agents. These complexes exhibit moderate antitumor activity in HeLa, MCF-7, HepG2, CNE-2, and A549 human tumor cells. Interestingly, all complexes showed higher cytotoxicity than cisplatin against a cisplatin-resistant cell line A549R, and less cytotoxicity on the nontumorigenic LO2 cells. Intracellular distribution studies suggest that these complexes are selectively localized in the mitochondria. Mechanism studies indicate that these complexes arrested the cell cycle in the G0/G1 phase and can influence mitochondrial integrity, inducing cancer cell death through reactive oxygen species (ROS)-dependent pathways.
Assuntos
Antineoplásicos/farmacologia , Guanidina/farmacologia , Irídio/farmacologia , Mitocôndrias/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Guanidina/química , Humanos , Irídio/química , Mitocôndrias/metabolismo , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Two ruthenium(II) complexes containing guanidinium ligands have been synthesized and characterized for the first time. It was found that the two complexes exhibit moderate antitumor activity in Hela, A549, CNE-2, MCF-7, and HepG2 human tumor cells. Flow cytometric analysis showed that both complexes arrested the cell cycle in the G2/M phase and induced apoptosis in Hela cells. Mechanism studies indicate that both complexes induced apoptosis through caspase- and reactive oxygen species (ROS)-dependent pathways. Additionally, the two complexes displayed higher phototoxicity to tumor cells and almost no influence on normal liver LO2 cells upon irradiation at 450nm.