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| Author(s): |
Mariana Medeiros
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2022-08-24 |
| Examining board members: |
Maria Sol Brassesco Annichini;
Andréia Machado Leopoldino;
Tiago Góss dos Santos
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| Advisor: | Maria Sol Brassesco Annichini |
| Abstract | |
Ewing\'s sarcoma (EWS) is a type of childhood bone neoplasm (0 to 19 years old), that accounts for about 2% of all childhood cancers. Treatment is mainly based on multidrug therapy, but in many cases, there is relapse and metastatic disease due to resistance. Thus, the search for new therapeutic targets is necessary. The nuclear transcription factor kappa B (NF-κB) is a good candidate as a regulator of several cellular processes. Therefore, the present study aimed to comparatively evaluate the therapeutic potential of NF-κB inhibition in SE by the inhibitors DHMEQ, DTCM-g, and SEMBL. For this, in silico analyzes and in vitro tests were performed after NF-κB inhibition in the TC-32 cell line. The results showed that SE samples present high expression of RELA, REL, and NFKB2 and low expression of NFKB1; in addition to SE-derived cell lines showing gene dependence on the NF-κB pathway. In in vitro tests, all NF-κB inhibitors were able to reduce cell viability in a dose-dependent manner, with SEMBL and DHMEQ being the most effective. In contrast, they showed little or no synergistic and additive effects when combined with Doxorubicin (DXR). Regarding migration, the three compounds were able to reduce it, with SEMBL being the most potent. In a 3D model, the NF-κB inhibitors increased the diameter of the spheroids as a result of the loss of integrity (sphericity). Inhibition of NF-κB also induced changes in gene expression of some NF-κB subunits (RELA, RELB, and NFKB1) and some of its molecular targets (BAX, PLAU, and MMP9). In this way, the NF-κB pathway, in general, presents itself as a good therapeutic target in SE and its inhibition leads to the reduction of cellular processes that promote it (viability, migration, integrity of the 3D structure) and increase of processes that inhibit (cell death) tumor progression. (AU) | |
| FAPESP's process: | 19/17020-0 - Comparative evaluation of antitumor effects of NF-ºB inhibitors DHMEQ, DTCM-g and SEMBL in Ewing's Sarcoma |
| Grantee: | Mariana Medeiros |
| Support Opportunities: | Scholarships in Brazil - Master |