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| Author(s): |
Adilson Kleber Ferreira
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2013-03-11 |
| Examining board members: |
Durvanei Augusto Maria;
Sergio Paulo Bydlowski;
Vera Luiza Capelozzi;
Rose Elí Grassi Rici;
Carlota de Oliveira Rangel Yagui
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| Advisor: | Durvanei Augusto Maria |
| Abstract | |
In this study, we evaluated the antitumor effects of synthetic phosphoethanolamine (FS) in an experimental tumor model and the signaling pathways involved in this activity. In vitro, FS was cytotoxic to tumor cell lines of human melanoma, SK- MEL-28, renal carcinoma murine, Renca, and for non-small cell lung cancer, NSCLC. Ultrastructural changes such as chromatin condensation, blubes formation on membranes and electrodense mitochondria were accompanied by a reduction of the mitochondrial electric potential. Increased activation of caspase-3, 8 and Bax protein expression, in addition to a reduction of CDK9 and CDK4/6 levels, was also observed. The reduction of migration and proliferation of endothelial cells, HUVEC, induced by FS was associated with the modulation of VEGF-A-expression, resulting in the in vitro inhibition of tubulogenesis. In vivo, FS was able to inhibit the growth of solid tumors of melanoma and renal carcinoma more potently than Dacarbazine (DITC) and Sunitinib. In the lung metastasis model, using RENCA cells, FS reduced the number of metastatic lung nodules and increased the survival rate of the animals. The therapeutic effects of FS were also evaluated in the model of acute promyelocytic leukemia transplanted in mice NOD/Scid. The treatment with FS reduced the number of peripheral blasts and infiltrates in the blood marrow, splenic and hepatic parenchyma. Fs was more potent than Daunorrubicine (DA) and all-trans retinoic acid (ATRA) in the induction of apoptosis in the malignant clones expressing CD34+ as well as CD117+/Gr-1+ cells. Taken together, theses results show that FS is a promising compound for the therapy against tumors (AU) | |