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Doctoral Thesis
DOI
https://doi.org/10.11606/T.60.2020.tde-21092021-054801
Document
Author
Full name
Patrícia Heloise Alves Bezerra
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2020
Supervisor
Committee
Torqueti, Maria Regina (President)
Barbisan, Luis Fernando
Fonseca, Maria Jose Vieira
Silva, Alfredo Ribeiro da
Amaral, Cristina Isabel Borges Dias
Reis, Francisco José Cândido dos
Title in Portuguese
Avaliação in vitro da associação farmacológica entre Genisteína e quimioterápicos no tratamento de câncer de mama
Keywords in Portuguese
Genisteína
Inibidores da aromatase
SERMs
Abstract in Portuguese
O câncer de mama é a neoplasia que mais acomete e a que mais mata mulheres no mundo. A abordagem terapêutica primária para este tipo de câncer na rede pública brasileira se dá através dos moduladores seletivos de receptores de estrógeno (SERMs), como o Tamoxifeno, e dos inibidores da enzima aromatase (IAs), como o Exemestano, Anastrozol e Letrozol. A grande problemática para esses tratamentos é o desenvolvimento de carcinomas resistentes à terapia convencional. Logo, a Genisteína, fitoestrógeno presente na soja, vem mostrando resultados antitumorais promissores. A fim de elucidar se a Genisteína possui efeito benéfico quando associada a esses quimioterápicos, esse trabalho se propôs a estudar o efeito combinado destes compostos através dos parâmetros de viabilidade celular, combinação farmacológica, progressão de ciclo celular, ativação de morte celular (apoptose, necrose e autofagia) e número de células-tronco tumorais (CTT) em 3 linhagens de câncer de mama: Luminal (MCF7), que superexpressa HER2 (SKBR3) e Triplo Negativo (MDAMB231), tendo como controle células epiteliais mamárias benignas (MCF10A). Além disso, também foram avaliados os efeitos combinados nas linhagens MCF7aro e LTEDaro, tendo como controle fibrosblastos humanos (HFF1). Dessa forma, os resultados mostraram que a dose de 100μM da Genisteína quando combinada aos metabólitos do Tamoxifeno diminui grandemente o IC50 dos metabólitos frente às linhagens MCF7 e MDAMB231, havendo sinergia, mas não à SKBR3, havendo, ainda, benefícios em relação à linhagem benigna. Assim, há indução de apoptose (vias intrínseca e extrínseca), diminuição de autofagia e maior retenção do ciclo celular nas linhagens tumorais quando tratadas com as combinações. Ainda, a combinação da Genisteína a 1μM potencializou os efeitos do Exemestano, mas não dos outros inibidores de aromatase (Anastrozol e Letrozol), através de promoção da atividade antiproliferativa, mas não pró-apoptótica, na linhagem MCF7aro, mas a isoflavona não mostrou efeitos significativos na linhagem LTEDaro. Finalmente, a combinação do Tamoxifeno e Exemestano com a Genisteína mostra-se um tratamento promissor diante de condições tumorais de mama específicas, tendo o potencial de diminuir os efeitos colaterais promovidos por tais quimioterápicos e alongar o período de não-resistência do tumor ao tratamento, devido à promoção de menores doses de quimioterápico.
Title in English
In vitro evaluation of the pharmacologic association between Genistein and chemotherapeutics in breast cancer treatment
Keywords in English
Aromatase inhibitors
Genistein
SERMs
Abstract in English
Breast cancer is the neoplasm that most affects and kills women in the world. The primary therapeutic approach for this type of cancer in the Brazilian public health system is through selective estrogen receptor modulators (SERMs), such as Tamoxifen, and aromatase inhibitors (AIs), such as Exemestane, Anastrozole and Letrozole. The major problem for these treatments is the development of carcinomas which are resistant to the conventional therapy. Genistein, a phytoestrogen present in soybeans, has shown promising antitumor results. In order to elucidate whether Genistein has a beneficial effect when associated with these chemotherapeutic agents, this study proposed to elucidate the combined effect of these compounds through the parameters of cell viability, pharmacological combination, cell cycle progression, activation of cell death (apoptosis, necrosis and autophagy) and number of cancer stem cells (CSCs) in 3 breast cancer cell lines: Luminal (MCF7), HER2-enhanced (SKBR3) and Triple Negative (MDAMB231), having benign breast epithelial cells (MCF10A) as control. In addition, the combined effects in MCF7aro and LTEDaro cell lines were also evaluated, having human fibroblasts (HFF1) as control. Thus, the present results showed that when combined with the metabolites of Tamoxifen, Genistein at the dose of 100μM greatly decreases the IC50 of the metabolites against the MCF7 and MDAMB231 cell lines, demonstrating synergy, but not for SKBR3, showing benefits in relation to the benign strain. Therefore, there was induction of apoptosis (intrinsic and extrinsic pathways), decreased autophagy and greater retention of the cell cycle in tumor cell lines when treated with the combinations. In addition, the combination of 1μM Genistein potentiated the effects of Exemestane, but not of the other aromatase inhibitors (Anastrozole and Letrozole), by promoting antiproliferative, but not pro-apoptotic, activity in the MCF7aro cell line, but the isoflavone did not show significant effects on the LTEDaro cell line. Finally, the combination of Tamoxifen and Exemestane with Genistein proves to be a promising treatment to specific breast tumors, having the potential to reduce the side effects caused by chemotherapeutic agents and to lengthen the period of non-resistance of the tumor to treatment, due to the promotion of lower doses of chemotherapy.
 
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Release Date
2022-11-26
Publishing Date
2021-09-22
 
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