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Modulating effects of mitochondrial activity of meclizine hydrochloridrate, 2,4-dinitrophenol and methyl--cyclodextrin associated with synthetic phosphoethanolamine in triple-negative breast cancer.

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Manuela Garcia Laveli da Silva
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
Defense date:
Examining board members:
Durvanei Augusto Maria; Vani Xavier de Oliveira Junior; Juliana Pereira
Advisor: Durvanei Augusto Maria

Breast cancer is the most common type of cancer among women in the world. Most breast cancer-related deaths are due to the rapid growth of tumors and the formation of metastases. Current therapies are limited and resistance to chemotherapy is an important obstacle to successful treatment. 2-Aminoethyl dihydrogen phosphate (2-AEH2P) is a monophosphoester that is involved in phospholipid turnover, with antiproliferative effects in a wide variety of tumor cell lines. The BR2 peptide is a non-specific cell penetration derivative derived from buforin IIb, having shown greater specificity to tumor cells. The effects of toxicity were evaluated and the MTT colorimetric test determined inhibitory concentration (IC50%). The morphological and structural changes involved in the apoptosis process were evaluated by marking the cytoskeleton with Fhalloidin and mitochondria with the MitoRED probe. The expression of markers involved in the pathways of cell death, proliferation, as well as mitochondrial electrical potential was assessed by flow cytometry. The results obtained showed that the BR2 peptide and the association 2-AEH2P+BR2 promoted greater toxicity in tumor lines, in comparison to the monophosphoester 2-AEH2P, in addition, the BR2 peptide promoted stop in the S phase for MDA tumor cell MB-231 and G0/G1 for the 4T1 tumor cell, while the association 2-AEH2P+BR2 caused a stop in the G0/G1 phases, in the 4T1 and MDA MB-231 tumor cells. MDA MB-231 tumor cells were sensitive to all treatments. The treatments led to changes in the morphology of the tumor cells, mainly in the mitochondria, which lose their integrity and reorganized in the perinuclear region, increasing the percentage of cells with inactive mitochondria. The treatments with the BR2 peptide and the association 2-AEH2P+BR2 were effective in inducing cell death, modulating the intrinsic pathway of apoptosis and promoting: reduced expression of CD44, CD34, CD24, cyclin D1, and Bcl-2 markers, increased p53, p21, Bax, and active 8 and 3 caspases and release of cytochrome c in tumor cells MDA MB-231. There was a considerable decrease in the proliferative response of tumor cells after treatments, corroborating the reduction in the expression of the PCNA marker. Reduction of the expression of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) was observed after treatments for tumor cells MDA MB-231. The association 2- AEH2P+BR2 proved to be more effective, providing modulation of proteins involved in regulated cell death and senescence, as well as selective cytotoxicity for tumor cells, compared to normal cells. (AU)

FAPESP's process: 16/15596-4 - MODULATORS EFFECTS OF MITOCHONDRIAL ACTIVITY of Meclizine Hydrochloride , 2,4-dinitrophenol, and METHYL-²-CYCLODEXTRIN ASSOCIATED WITH SYNTHETIC phosphoethanolamine in TRIPLE negative BREAST CANCER
Grantee:Manuela Garcia Laveli da Silva
Support Opportunities: Scholarships in Brazil - Doctorate