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MODULATORS EFFECTS OF MITOCHONDRIAL ACTIVITY of Meclizine Hydrochloride , 2,4-dinitrophenol, and METHYL-²-CYCLODEXTRIN ASSOCIATED WITH SYNTHETIC phosphoethanolamine in TRIPLE negative BREAST CANCER

Grant number: 16/15596-4
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2017
Effective date (End): February 29, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Durvanei Augusto Maria
Grantee:Manuela Garcia Laveli da Silva
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Breast cancer is the second most deadly cancer for women worldwide, despite the various conventional approaches to radiotherapy, chemotherapy and hormone therapy. The resistance of tumor cells to chemotherapy is a major obstacle to the clinical success of cancer therapy. Triple-negative breast tumor is more aggressive than other subtypes of human breast cancer. The tumors that have higher spread for solid organs such as liver and lung, and in more recent studies observed a higher incidence of brain metastases. Synthetic phosphoethanolamine is a phosphorylated molecule artificially, which makes it different from existing molecules for their absorption level of about 90% with anti-inflammatory and pro-apoptotic properties. Meclizine is an antihistamine used against nausea and dizziness, as well as many antihistamines have anticholinergic. 2,4-dinitrophenol is a chemical uncoupler which acts in lowering the mitochondrial membrane potential without modifying ATP synthesis. Methyl-²-cyclodextrin belongs to the family being able to remove cholesterol from the plasma membrane. The effects on mitochondria caused by the synthetic phosphoethanolamine associated with the compounds in the tumor cell line will be evaluated by the MTT colorimetric assay and obtain IC50%. It will evaluate the production of free radicals by LPO test and will be quantified ROS production. Changes in cell death pathways will be evaluated by flow cytometry. Changes in cellular structures by transmission microscopy and confocal laser. Marking of lysosomal vesicles by acridine-orange and evaluation of the mitochondrial electrical potential by rhodamine-123 probe and the JC-1 probe. The cytoskeleton arrangement by labeling with phalloidin- FITC. The caveolin-1 will be checked and evaluated by the anti-caveolina1 antibody. ATP and ADP production levels will be measured using ATP/ADP kit (Sigma-Aldrich).