Efeito dos sesquiterpenos α-humuleno e β-cariofileno sobre linhagens celulares derivadas de carcinomas mamários
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Data
2019-09-30
Autores
Barbosa, Barbara Mitsuyasu [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
O carcinoma mamário é o tipo de câncer mais frequente entre as mulheres, com estimativas de aumento de sua incidência mundial nas próximas décadas. O câncer de mama triplo negativo (CMTN) é um subtipo definido pela falta de receptores para os hormônios estrógeno e progesterona e sem superexpressão de HER-2. Ocorre geralmente em mulheres com menos de 50 anos e está relacionado a uma alta taxa de recorrência e mortalidade. As terapias convencionais são hormônio-dependentes ou possuem a proteína HER2 como alvo, logo o CMTN não é responsivo a essas modalidades terapêuticas. Devido a biologia deste tumor, novas abordagens são necessárias para o seu tratamento. Plantas são importantes fontes de compostos antitumorais. Os sesquiterpenos α-humuleno (HUM) e β-cariofileno (CAR) geralmente estão presentes em conjunto no óleo essencial de diversas plantas. Um número limitado de estudos foi realizado sobre os seus efeitos em células derivadas de carcinomas mamários, porém um efeito imunomodulador foi descrito para diferentes sesquiterpenos em células derivadas de cânceres humano. A hipótese desse estudo é que os efeitos in vitro dos sesquiterpenos HUM e CAR nas linhas celulares derivadas de CMTP são mediados por alterações nos níveis de expressão de citocinas produzidas pelas células tumorais. Foram selecionadas quatro linhagens celulares triplo-negativas (BT-20, BT-549, MDA-MB-231 e MDA-MB-436). Inicialmente, os efeitos isolados ou combinados do HUM e CAR foram avaliados pelo ensaio de viabilidade celular pelo teste de MTT em diferentes concentrações (6,25; 12,5; 25; 50 e 100 µM), após 24, 48, 72 e 96 horas de exposição. Com base nos resultados, a linhagem celular BT-20 foi selecionada para os experimentos subsequentes. A proliferação e migração celular foi avaliada pelo scratch assay e os níveis relativos de expressão do gene CXCL8 foram determinados por RT-PCR quantitativa em tempo real. Os sesquiterpenos HUM e CAR têm baixo potencial citotóxico nas linhagens derivadas de CMTNs e nenhum efeito na migração das células BT-20. Além disso, o α-humuleno foi capaz de aumentar os níveis de transcrição do gene CXCL8, que codifica IL-8, nessa linhagem celular. Como essa quimiocina foi associada a atividades de promoção de tumores, nossos resultados sugerem que esses sesquiterpenos não são úteis para as novas estratégias terapêuticas do câncer.
Breast cancer is the most common type of cancer amongst women. Worldwide, its incidence is estimated to increase in the coming decades. Triple negative breast cancer (TNBC) is a subtype defined by the absence of receptors for estrogen and progesterone hormones and without HER-2 overexpression. It usually occurs in women under 50 years old and it is related to a high recurrence and mortality rates. As conventional therapies are hormone-dependent or target HER2, TNBC are not responsive to these therapeutic approaches. Due to the biology of this tumor, new targets are needed for its treatment. Plants are important sources of antitumor compounds, the sesquiterpenes α-humulene (HUM) and β-caryophyllene (CAR) are usually present together in the essential oil of several plants. Few studies have been conducted on their effect in breast cancer cells, but an immunomodulatory effect of different sesquiterpenes was described on human cancer cells. The hypothesis of this study is that the in vitro effects of sesquiterpenes HUM and CAR on cell lines derived from TNBC are mediated by changes in cytokine expression levels produced by tumor cells. For this, four triple-negative cell lines were selected (BT-20, BT-549, MDA-MB-231, and MDA-MB-436). Initially, the isolated or combined effects of HUM and CAR were evaluated by the MTT cell viability assay upon different concentrations (6.25, 12.5, 25, 50, and 100µM), after 24, 48, 72, and 96 hours of exposure. Based on the effect of the sesquiterpenes treatment in cell viability, the BT-20 cell line was chosen for the subsequent experiments. Cell migration was evaluated by scratch assay and relative expression levels of the gene CXCL8 were determined by quantitative real-time RT-PCR. The sesquiterpenes HUM and CAR have poor cytotoxic potential on triple-negative breast cancer cells and no effects on the migration of BT-20 cells. In addition, α-humulene was able to increase the transcriptional levels of the gene CXCL8, encoding IL-8. Since this chemokine has been associated with tumor-promoting activities, our findings suggest that these sesquiterpenes are not useful for new therapeutic strategies of cancer.
Breast cancer is the most common type of cancer amongst women. Worldwide, its incidence is estimated to increase in the coming decades. Triple negative breast cancer (TNBC) is a subtype defined by the absence of receptors for estrogen and progesterone hormones and without HER-2 overexpression. It usually occurs in women under 50 years old and it is related to a high recurrence and mortality rates. As conventional therapies are hormone-dependent or target HER2, TNBC are not responsive to these therapeutic approaches. Due to the biology of this tumor, new targets are needed for its treatment. Plants are important sources of antitumor compounds, the sesquiterpenes α-humulene (HUM) and β-caryophyllene (CAR) are usually present together in the essential oil of several plants. Few studies have been conducted on their effect in breast cancer cells, but an immunomodulatory effect of different sesquiterpenes was described on human cancer cells. The hypothesis of this study is that the in vitro effects of sesquiterpenes HUM and CAR on cell lines derived from TNBC are mediated by changes in cytokine expression levels produced by tumor cells. For this, four triple-negative cell lines were selected (BT-20, BT-549, MDA-MB-231, and MDA-MB-436). Initially, the isolated or combined effects of HUM and CAR were evaluated by the MTT cell viability assay upon different concentrations (6.25, 12.5, 25, 50, and 100µM), after 24, 48, 72, and 96 hours of exposure. Based on the effect of the sesquiterpenes treatment in cell viability, the BT-20 cell line was chosen for the subsequent experiments. Cell migration was evaluated by scratch assay and relative expression levels of the gene CXCL8 were determined by quantitative real-time RT-PCR. The sesquiterpenes HUM and CAR have poor cytotoxic potential on triple-negative breast cancer cells and no effects on the migration of BT-20 cells. In addition, α-humulene was able to increase the transcriptional levels of the gene CXCL8, encoding IL-8. Since this chemokine has been associated with tumor-promoting activities, our findings suggest that these sesquiterpenes are not useful for new therapeutic strategies of cancer.
Descrição
Palavras-chave
CXCL8, Câncer de mama triplo negativo, Expressão gênica, IL-8, Terpenos