Estudo do efeito antitumoral da associação da metformina com a nanoparticula de Poli(ácido lático-co-glicólico) de metotrexato em células de adenocarcinoma ductal pancreático
Pancreatic ductal adenocarcinoma (PDAC) corresponds to 90% of malignant pancreatic tumors and one of the main risk factors for this cancer is type 2 diabetes mellitus, as well as smoking and obesity. Metformin is an oral anti-glycemic widely used in the treatment of diabetes mellitus. In addition...
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| Formato: | Dissertação |
| Idioma: | pt_BR |
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Universidade Federal do Rio Grande do Norte
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| Endereço do item: | https://repositorio.ufrn.br/handle/123456789/31251 |
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| Resumo: | Pancreatic ductal adenocarcinoma (PDAC) corresponds to 90% of malignant
pancreatic tumors and one of the main risk factors for this cancer is type 2 diabetes
mellitus, as well as smoking and obesity. Metformin is an oral anti-glycemic widely
used in the treatment of diabetes mellitus. In addition to this property of use, metformin
has recently been reported to have antitumor activity. The aim of this study was to
perform the in vitro evaluation of the pró-apoptotic effect by combining metformin and
methotrexate-associated PLGA nanoparticle, a standard chemotherapy used in
antineoplastic treatment. To this end, Alamar Blue viability tests, annexin / PI flow
cytometry and immunofluorescence with anti-caspase-3, anti-bcl-2, and anti-FADD
antibodies in pancreatic ductal adenocarcinoma (PANC-1) cells were performed. and
in human kidney embryonic cells (HEK-293). The internalization of FITC-labeled
nanoparticles by immunofluorescence was also evaluated. Evaluation of drug
resistance and cell survival pathway were done by analyzing mRNA expression of the
MDR1, survivin, EGFR, Akt, and mTOR genes by RT-PCR. The results showed that
isolated doses of metformin and nanoparticle do not induce significant apoptosis,
however, the combined use induced up to 55.3% of apoptosis. The high expression of
FADD and caspase-3 was statistically significant with p <0.01, as well as the low
expression of bcl-2, with p <0.05, in the 48 hours period when combined with metformin
and PLGA- MTX, showing activation of apoptosis by both extrinsic and intrinsic
pathways. Moreover, the increase of GSH and reduction of MDA reveal antioxidant
effect of treatment in both strains. Nanoparticles reduced MDR1, survivin, EGFR drug
resistance gene expression with p <0.0001 in all combination treatments and also
reduced Akt and mTOR survival life gene expression with p <0.0001 in all treatments.
all treatments combined. The use of metformin prior to PLGA-MTX increases tumor
cell apoptosis induction, reduces resistance to antitumor treatment and inhibits cell
survival pathways. In this context, it is concluded that metformin enhances the
antitumor activity of PLGA-MTX, suggesting that it is a promising integrated system in
the future when used in combination within a nanoparticle system. |
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