RESUMO
There is much interest in understanding the mechanisms by which platinum-based anticancer agents enter cells, and the copper transporter CTR1 has been the focus of many recent studies. While there is a clinical correlation between CTR1 levels and platinum efficacy, cellular studies have provided conflicting evidence relating to the relationship between cisplatin and CTR1. We report here our studies of the relationship between cisplatin and copper homeostasis in human colon cancer cells. While the accumulation of copper and platinum do not appear to compete with each other, we did observe that cisplatin perturbs CTR1 distribution within 10 min, a far shorter incubation time than commonly employed in cellular studies of cisplatin. Furthermore, on these short time-scales, cisplatin caused an increase in the cytoplasmic labile copper pool. While the predominant focus of studies to date has been on CTR1, these studies highlight the importance of investigating the interaction of cisplatin with other copper proteins.
Assuntos
Proteínas de Transporte de Cátions/metabolismo , Cisplatino/metabolismo , Neoplasias do Colo/metabolismo , Proteínas de Transporte de Cátions/química , Sobrevivência Celular , Cisplatino/química , Neoplasias do Colo/patologia , Cobre/metabolismo , Cobre/farmacocinética , Transportador de Cobre 1 , Relação Dose-Resposta a Droga , Homeostase , Humanos , Platina/metabolismo , Platina/farmacocinética , Relação Estrutura-AtividadeRESUMO
Copper plays a key role in the modulation of cellular function, defence, and growth. Here we present InCCu1, a ratiometric fluorescent sensor for mitochondrial copper, which changes from red to blue emission in the presence of Cu(i). Employing this probe in microscopy and flow cytometry, we show that cisplatin-treated cells have an impaired ability to accumulate copper in the mitochondria.
Assuntos
Técnicas Biossensoriais/métodos , Cobre/metabolismo , Corantes Fluorescentes/metabolismo , Mitocôndrias/metabolismo , Espectrometria de Fluorescência/métodos , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Células HeLa , Humanos , Mitocôndrias/efeitos dos fármacosRESUMO
The partition and self-assembly of a new generation of cyclic peptide-polymer conjugates into well-defined phospholipid trans-bilayer channels is presented. By varying the structural parameters of the cyclic peptide-polymer conjugates through the ligation of hydrophobic and hydrophilic polymers, both the structure of the artificial channels using large unilamellar vesicle assays and the structural parameters required for phospholipid bilayer partitioning are elucidated. In addition, temperature was used as an external stimulus for the modulation of transbilayer channel formation without requiring the redesign and synthesis of the cyclic peptide core. The thermoresponsive character of the cyclic peptide-polymer conjugates lays the foundation for on-demand control over phospholipid transmembrane transport, which could lead to viable alternatives to current transport systems that traditionally rely on endocytic pathways.