ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Antioxidants/metabolism , Tumor Suppressor Protein p53/physiology , Apoptosis/drug effects , Apoptosis/genetics , Catalase/drug effects , Catalase/genetics , Cell Survival/drug effects , Cell Survival/genetics , Cyclin-Dependent Kinase Inhibitor p21/genetics , DNA Repair Enzymes/genetics , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Oxidative Stress/drug effects , Oxidative Stress/genetics , Reactive Oxygen Species/metabolism , Superoxide Dismutase/drug effects , Superoxide Dismutase/genetics , Tumor Suppressor Protein p53/geneticsABSTRACT
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.
Subject(s)
Cytomegalovirus/physiology , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , Leukemia/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism , Antibiotics, Antineoplastic/pharmacology , Cell Survival/drug effects , Drug Synergism , Humans , Sirolimus/pharmacology , THP-1 CellsABSTRACT
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.