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NEW ACRIDINE THIOUREA GOLD(I) COMPLEXES AS DNA INTERCALATORS, ANTICANCER AGENTS AND VASCULOGENIC MIMICRY INHIBITORS
Autores:
SERGIO ALEJO PÉREZ HENAREJOS
,
CONCEPCIÓN DE HARO GARCÍA
,
CONSUELO VICENTE LÓPEZ
,
ANTONIO DONAIRE GONZÁLEZ
,
ANA ZAMORA MARTÍNEZ
,
GLORIA VIGUERAS BAUTISTA
, VIKTOR BRABEC, DELIA BAUTISTA,
JOSE RUIZ LÓPEZ
,
Grupos de investigación:
[GI/IMIB/E110/2011] Metalofámacos antitumorales no convencionales
Comunicación:
Antecedentes:
Platinum based metallodrugs such as cisplatin (CDDP) and carboplatin have become established chemotherapeutics for applying to various types of cancers. However the clinical use is limited by high toxicity, severe side-effects and drug resistance. On the other hand metastasis is a complicated, multi-step process still poorly understood. Cell migration and invasion are the early crucial steps of the metastatic cascade. Angiogenesis is a hallmark of tumor development and metastasis, and then a possible target. In order to overcome these disadvantages, Two new 1-acridin-9-yl-3-methylthiourea gold(I) DNA intercalators [Au(ACRTU)2]Cl (2) and [Au(ACRTU)(PPh3)]PF6 (3) have been prepared.
Métodos:
A serial of chemical and biological methods has been used. Both complexes were characterized by positive-ion ESI-MS, NMR spectroscopy, IR, UV-Vis spectroscopy, linear and circular dichroism. Biological experiments were performed by MTT assay (IC50), Flow cytometry (cell cycle, apoptosis, Caspase-3, ROS induction), Confocal and Electron microscopy (intracellular localization) and agarose gel.
Resultados:
Both compounds are highly active in human ovarian carcinoma cisplatin-sensitive A2780 cells, exhibiting IC50 values in the sub-micromolar range. 2 and 3 are also very cytotoxic toward different phenotypes of breast tumor cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ER?? and ER??) and MCF-7 (ER+). Both complexes are able to induce apoptosis through activation of caspase 3 in vitro. Although it is generally accepted that the mechanisms of action of gold compounds implicate interactions with a variety of targeted proteins inside cells, 2 and 3 present a DNA-dependent mechanism of action. They locate in the nucleus in MCF-7 cells according to confocal microscopy and transmission electronic microscopy. The binding to DNA resulted to be via intercalation as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent effect on topoisomerase I mediated DNA unwinding. In addition, 2 and 3 exhibit potent antiangiogenic effects, able to also inhibit vasculogenic mimicry of highly invasive MDA-MB-231 breast cancer cells.
Conclusiones:
Two new 1-acridin-9-yl-3-methylthiourea gold(I) anticancer complexes [Au(ACRTU)2]Cl (2) and [Au(ACRTU)(PPh3)]PF6 (3) have been prepared. According to confocal luminiscence imaging both complexes are located in the nucleus in MCF-7 cells. 2 and 3 inhibit vasculogenic mimicry of highly invasive MDA-MB-231 breast cancer cells,, and diminish the mobility of and diminish mobility in MDA-MB-231 as studied by wound healing scratch assay.
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