RESUMO
The effect of inhibition of the tumor suppressor p53 on the antioxidant system genes expression under the influence of cytotoxic compounds of the platinum group was studied. It was found that the action of platinum(II) and platinum(IV) complexes induced accumulation of p53 protein with a maximum in 12 h, which was confirmed by an increase in the expression of the P21 gene, the target gene of the p53 protein. It was shown that the action of platinum complexes activated the expression of catalase and superoxide dismutase 2 genes. Suppression of p53 protein functions with specific inhibitor α-piphitrin under the action of platinum complexes reduced the expression of catalase and superoxide dismutase 2 genes and the target gene P21, which attested to the p53-dependent regulation of these genes.
Assuntos
Antineoplásicos/farmacologia , Antioxidantes/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Catalase/efeitos dos fármacos , Catalase/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Enzimas Reparadoras do DNA/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Results obtained showed that infection with HCMV prevented the death of THP-1 cells treated with DOX in both active and latent forms of infection. In the presence of mTOR inhibitors (rapamycin and Torin2), the sensitivity of the infected cells to DOX was restored. Rapamycin inhibited the expression of the HCMV protein IE1-p72 and increased sensitivity to DOX. Molecular targets for the creation of new drugs for the treatment of leukemia in patients infected with HCMV were determined.
Assuntos
Citomegalovirus/fisiologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Antibióticos Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Sirolimo/farmacologia , Células THP-1RESUMO
It has been revealed for the first time that sodium fullerenolate Na(4)[C(60)(OH)(â¼30)] (NaFL), a water soluble polyhydroxylated [60]fullerene derivative, destroys amyloid fibrils of the Aß(1-42) peptide in the brain and prevents their formation in in vitro experiments. The cytotoxicity of NaFL was found to be negligibly low with respect to nine different culture cell lines. At the same time, NaFL showed a very low acute toxicity in vivo. The maximal tolerable dose (MTD) and LD50 for NaFL correspond to 1000 mg kg(-1) and 1800 mg kg(-1), respectively, as revealed by in vivo tests in mice using intraperitoneal drug injection. The observed pronounced anti-amyloid activity and low toxicity of NaFL make it a very promising lead drug for the development of potent fullerene-based therapeutic approaches for the treatment of amyloidoses, such as Alzheimer's disease and others.