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Master's Dissertation
DOI
https://doi.org/10.11606/D.5.2022.tde-03102022-114101
Document
Author
Full name
Monique Gonçalves Alves
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2022
Supervisor
Committee
Maria, Durvanei Augusto (President)
Bendit, Israel
Gomes, Ligia Ferreira
Oliveira Junior, Vani Xavier de
Title in Portuguese
Avaliação farmacológica sinérgica do composto monofosfoester 2-AEH2F associado com fármacos envolvidos no metabolismo tumoral no modelo de carcinomatose de mama de Ehrlich
Keywords in Portuguese
2-AEH2F
Apoptose
Câncer de mama
DNA fragmentado
Fosfolipídio
Progressão do ciclo celular
Abstract in Portuguese
O fosfolipídio sintético 2-aminoetil dihidrogênio fosfato (2-AEH2F) é um precursor lipídico, éster fosfórico amino-etil, que em estudos anteriores realizados por nosso grupo mostraram um potencial citotóxico em diversas linhagens tumorais: células de melanoma murino B16F10, células de câncer de mama MCF-7 e células leucêmicas humanas K562, sem afetar a viabilidade e a capacidade proliferativa das células normais. Fármacos utilizados na prática clínica são candidatos viáveis para a terapia combinada devido às suas interações inibitórias ou moduladoras sobre o metabolismo tumoral, ou mesmo diretamente potencializando a atividade tumoral de outras drogas combinadas. Portanto, o objetivo deste trabalho foi avaliar o potencial antiproliferativo,sinérgico, antitumoral e pró- apoptótico das associações entre o composto 2-AEH2F e os seguintes fármacos: Sinvastatina, Metformina, GM-CSF, Cloridrato de Meclizina, Coenzima Q10, Paclitaxel, Ácido Lipóico e 2,4-Dinitrofenol, no modelo in vitro de carcinomatose mamária ascítica de Ehrlich. Foram realizados neste estudo a determinação da atividade citotóxica pelo método colorimétrico de MTT; a análise das fases do ciclo celular; do potencial elétrico mitocondrial, de checagem do ciclo celular e apoptose, em células do tumor ascítico de Ehrlich (EAT) em comparação às células de fibroblasto murino L929. Bem como a expressão de marcadores nas células. Os resultados mostraram que o composto 2-AEH2F associado aos fármacos GM-CSF, Sinvastatina e Coenzima Q10 apresentaram efeitos sinérgico e aditivo, respectivamente, que foram capazes de aumentar a quantidade de DNA fragmentado, modular a progressão das fases do ciclo celular e potencializar os efeitos citotóxicos contra as células tumorais. Além disso, o tratamento 2-AEH2F em combinação com o quimioterápico Paclitaxel apresentou a maior redução do potencial elétrico mitocondrial em células tumorais (EAT). O 2-AEH2F foi capaz de modular a expressão dos marcadores para um perfil de resposta pró-inflamatória isoladamente ou em associação com os outros fármacos, demonstrando o seu potencial no controle da proliferação celular in vitro no modelo do tumor ascítico de Ehrlich
Title in English
Synergistic pharmacological evaluation of the monophosphoester compound 2-AEH2F associated with drugs involved in tumor metabolism in the Ehrlich model of breast carcinomatosis
Keywords in English
2-AEH2F
Breast cancer
Metabolic therapy
Therapeutic association
Abstract in English
The antineoplastic phospholipid 2-aminoethyl dihydrogen phosphate (2-AEH2F) is a lipid precursor, amino-ethyl phosphoric ester, which in previous studies has shown to have cytotoxic potential against B16F10 murine melanoma cells, MCF-7 breast cancer cells, leukemic cells and capable of altering macrophage metabolism and inhibiting tumor growth by inducing apoptosis. In addition, some conventional drugs used in clinical practice are considered viable candidates for combination therapies due to their inhibitory and modulating activities of cellular metabolism or antitumor. Therefore, the objective of this work was to evaluate the antiproliferative, antitumor and pro-apoptotic potential of the association between the compound 2-AEH2F and the drugs Simvastatin, Metformin, GM-CSF, Meclizine Hydrochloride, Coenzyme Q10, Paclitaxel, Lipoic Acid and 2,4-Dinitrophenol in the in vitro model of Ehrlich's ascitic mammary carcinomatosis. For this, the tests for Determination of cytotoxic activity by the MTT method, the analysis of the phases of the cell cycle, fragmented DNA, the pharmacological effects of the associations and the mitochondrial electrical potential were evaluated in normal murine fibroblast cells (L929) and in tumor cells. Ehrlich ascites (EAT), the expression of markers in tumor cells was subsequently evaluated. The results indicate that the compound 2-AEH2F associated with the drugs GM-CSF, Simvastatin and Coenzyme Q10 showed synergistic and additive effects, respectively, there was also an increase in fragmented DNA, ability to modulate the progression of cell cycle phases and increased effects antiproliferative and cytotoxic against Ehrlich ascites tumor cells. Furthermore, the 2-AEH2F + Paclitaxel(12h) group showed the greatest reduction in mitochondrial electrical potential in tumor cells and we observed that 2-AEH2F modulates the expression of markers for a pro-inflammatory response both alone and co-administered with other drugs
 
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Publishing Date
2022-10-19
 
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