| 摘要 |
<p>The invention describes the use of the complex copper (Á4-Oxo) tetra-Á4-acetate {4-hydroxy-3,5-bis(morpholinomethyl)} tetra copper (II) (CCu-COP) for treating cervical cancer. This CCu-COP showed to be cytotoxic in 4 different cellular lines of cervical cancer, where the cellular line with the most sensitivity to the treatment of 24 hours at concentrations of from about 25 to 100 um was HeLa. The CCu-COP induces changes in the membrane of HeLa cells, where after 6 hours of treatment it was possible to detect Annexin V coupled to FITC as an indicator of the translocation of phosphatidylserine to the outer surface of the membrane. The treatment of HeLa cells with the CCu-COP possibly induced the activation of the intrinsic pathway of apoptosis, since a reduction in the procaspase-7 was observed with respect to the incubation time with CCu-COP, also showing an increase of cytochrome C in the cytoplasm, which is an indicative of permeability in the outer mitochondrial membrane. Caspase-3 could not be detected in the total extracts of HeLa treated with 74.74 um of CCu-COP, but it was detected in the cells treated with 20 um of cis-Platinum, which suggests that CCu-COP may be inducing a way of cellular death different from traditional apoptotic pathways. The cytotoxicity of the compound is related to its ability to induce peroxidation of lipids at concentrations ranging from 5 um to 20 um, which was detected by the TBARS evaluation. The CCu-COP showed a dual effect in the inhibition of lipid peroxidation induced with FeSO4, since at lower concentrations of 13.34 uM it acts synergistically with iron sulfate and increases the TBARS levels while at higher concentrations of 23.7 uM it will inhibit the peroxidation induced with FeSO4. This CCu-COP resulted to be not mutagenic in the Ames test performed in the strains TA98, TA100 and TA102 of Salmonella typhimurium at concentrations of 50, 100 and 200 uM, nor genotoxic upon evaluating the presence of micro-cores formed in per ipheral blood after the administration of a dose of the complex, where the highest concentration evaluated was of 15 mg/kg by weight in mice CD1. The delay on the tumor growth induced by 0.81 mg/kg and 8.1 mg/Kg of CCu-COP at day 16th of treatment in nude mice obeys to a reduction in the differential expression of genes related to the proliferation, metastasis and angiogenesis that this CCu-COP compound induces in tumors of cervical cancer. Finally, the histopathological study of samples of liver, spleen and kidney of mice with induced tumors that were treated with CCu-COP or cis-Platinum showed that the CCU-COP caused fewer damages to the tissue structures of the aforementioned organs, while confirming the high nephrotoxic effect of the cis-Platinum, so that it is concluded that the CCu-COP has potential as an antitumor drug against cervical cancer.</p> |
