RESUMO
Acridine derivatives, such as amsacrine, represent a well known class of multi-targeted anti-cancer agents that generally interfere with DNA synthesis and inhibit topoisomerase II. But in addition, these tricyclic molecules often display secondary effects on other biochemical pathways including protein metabolism. In order to identify novel anti-cancer drugs, we evaluated the mechanism of action of a novel series of bis- and tetra-acridines. As expected, these molecules were found to interact with DNA and inhibit the topoisomerase II-mediated DNA decatenation. Interestingly when tested on human tumour cells either sensitive (HL-60) or resistant (HL-60/MX2) to topoisomerase II inhibitors, these molecules proved equicytotoxic against the two cell lines, suggesting that they do not only rely on topoisomerase II inhibition to exert their cytotoxic effects. In order to identify alternative targets, we tested the capacity of acridines 1-9 to inhibit the proteasome machinery. Four tetra-acridines inhibited the proteasome in vitro, with IC(50) values up to 40 times lower than that of the reference proteasome inhibitor lactacystin. Moreover, unlike peptide aldehydes used as reference inhibitors for the proteasome, these new acridine compounds demonstrated a good selectivity towards the proteasome, when tested against four unrelated proteases. A cellular assay based on the degradation of a proteasome protein substrate indicated that at least two of the tetra-acridines maintained this proteasome inhibition activity in a cellular context. This is the first report of tetra-acridines that demonstrate dual topoisomerase II and proteasome inhibition properties. This new dual activity could represent a novel anti-cancer approach to circumvent certain forms of tumour resistance.
Assuntos
Acridinas/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Proteassoma , Inibidores da Topoisomerase II , Acridinas/síntese química , Acridinas/química , Acridinas/classificação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/classificação , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/classificação , Células HL-60 , Humanos , Concentração Inibidora 50 , Leucemia Promielocítica Aguda/tratamento farmacológico , Modelos Biológicos , Estrutura Molecular , Complexo de Endopeptidases do Proteassoma/análise , Sensibilidade e Especificidade , Relação Estrutura-AtividadeRESUMO
El objetivo de este trabajo es describir la conducta alimentaria y características asociadas en una población de niños y adolescentes chilenos, que consultan al programa de trastornos alimentarios de la PUC.
