Evaluación pre-clínica del compuesto T44Bf como potencial agente antitumoral para el tratamiento de leucemias agudas humanas
Lead optimization process obtained from a phenotypic strategy, requires the characterization of the molecular mechanism of action involved. From a phenotypic screening previously performed on a group of compounds belonging to the family of thiosemicarbazones (TSCs), we have previously identified 4,4...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2016
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_1173 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_1173.dir/1173.PDF |
| Aporte de: |
| Sumario: | Lead optimization process obtained from a phenotypic strategy, requires the characterization of the molecular mechanism of action involved. From a phenotypic screening previously performed on a group of compounds belonging to the family of thiosemicarbazones (TSCs), we have previously identified 4,4'-dimethoxybenzophenone thiosemicarbazone (T44Bf) as a lead compound in the U937 cell line. The characterization of the mechanism of action of T44Bf conducted on a panel of human leukemia cell lines (U937, HL60, Jurkat and KG1a) showed that T44Bf-mediated antiproliferative effects are associated with a reversible chronic mitotic arrest caused by inhibition of microtubules polymerization, followed by induced programmed cell death. Furthermore, T44Bf selectively induces apoptosis in leukemia cell lines when compared to differentiated hematopoietic cells. Also, apoptotic activity was associated with loss of mitochondrial membrane potential, and sustained phosphorylation of anti-apoptotic protein Bcl-2 and Bcl-xL as well as increased pro-apoptotic protein Bad levels. In addition, ERK signaling pathway activation was found to be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and allow a rational establishment of a method for the development of this lead compound optimization. |
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