Avaliação da atividade biológica de um terpeno em linhagem de câncer de pulmão de pequenas células (A549)
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2018-06-20
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Goettert, Márcia Inês
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O câncer se trata de uma das principais causas de mortes no mundo, sendo o câncer de pulmão o primeiro em incidência mundial. No Brasil, o câncer de pulmão é o segundo principal responsável por mortes por câncer em homens (após câncer de próstata) e o quarto em mulheres - sendo o Rio Grande do Sul o segundo estado brasileiro com maior incidência de casos de câncer. Caracterizado pelo crescimento desordenado e desenfreado de células, o desenvolvimento tumoral é definido pela evasão da morte celular e tem sido intimamente correlacionado à inflamação. Tratamentos usuais do câncer, como quimioterapia e radioterapia, apresentam elevados efeitos adversos ao paciente, além do alto custo. Tendo em vista que a maior parte das drogas antineoplásicas produzidas são oriundas de compostos naturais ou de seus derivados, é constante a busca por novos metabólitos de origem natural, em especial os de origem vegetal - que apresentam potencial na busca por novas moléculas para síntese de fármacos. Diversos fitocomponentes, como o terpeno α-terpineol (TPN), apresentam efeito antiproliferativo e anticancerígeno em linhagens de adenocarcinoma de mama, próstata e ovário, e leucêmicas. Neste trabalho foi avaliado o potencial anti-proliferativo do TPN frente à seis linhagens tumorais humanas (A549, MCF-7, HT-29, Caco-2, LNCaP, ACP-03), sendo a A549 (câncer de pulmão) selecionada para experimentos de tratamento repetido por seis dias em associação com o quimioterápico doxorrubicina (DOXO). O mecanismo de morte celular, marcadores moleculares, atividade
enzimática (JAK-3, JNK-3, p38-α), migração celular e inibição de TNF-α foram avaliados. Dentre as seis linhagens analisadas, três (A549, MCF-7, HT-29) apresentaram redução significativa da viabilidade celular após tratamento com o TPN por 48 h. A associação do TPN com a DOXO na linhagem A549 potencializou o efeito anti-proliferativo em comparação com a DOXO. Após seis dias de tratamento observou-se comportamento dose- e tempo-dependente da DOXO e do TPN sem apresentar diferença estatística entre eles. O TPN apresentou atividade inibitória da p38-α (IC50=729 μ M) e JAK3 (IC50=6,3 μM). Após 48 h de
tratamento, observou-se e necrose nas células tratadas com DOXO (21,5 %) e TPN (7,3 %).Com a associação de ambas as drogas, a taxa de necrose elevou-se para 33,5 %, bem como para os seis dias de tratamento (52,3 %). Observou-se ainda, redução da migração celular após 120 h de tratamento com o TPN em comparação ao controle. Com base no exposto acima, o TPN apresenta potencial como biomolécula para o desenvolvimento de novos fármacos ou mesmo seu uso, como coadjuvante no tratamento de câncer de pulmão humano.
Cancer is one of the leading causes of death worldwide, with lung cancer as the major one. In Brazil, lung cancer is the second leading cause of cancer deaths in men (after the prostate cancer) and fourth in women. Rio Grande do Sul is the second Brazilian state with the highest incidence of cancer. Characterized by disordered cell growth, tumor development is defined by cell death evasion and has been closely correlated to inflammation. Standard cancer treatments, such as chemotherapy and radiotherapy, cause adverse effects on patients. Considering that most of the antineoplastic drugs produced are derived from natural compounds or their derivatives, natural products (especially those of plant origin) present potential in the search for new molecules for drug synthesis. Several phytoconstituents, such as the terpene α-terpineol (TPN), have antiproliferative and anticancer effects in cell lines of breast, prostate and ovary carcinomas, and leukemic cells. In the present study, the anti-proliferative potential of TPN on six human tumor cell lines (A549, MCF-7, HT-29, Caco-2, LNCaP and ACP-03) was evaluated. The A549 cell line (lung adenocarcinoma) was selected for experiments of six days with TPN and doxorubicin (DOXO) co-treatment. Mechanisms of cell death, molecular markers, enzymatic activity (JAK-3, JNK-3, p38-α), cell migration and inhibition of TNF-α were evaluated. Among the six lines, three of them (A549, MCF-7, HT-29) have shown a significant reduction of cell viability after 48 h treatment with TPN. Co-treatment of TPN and DOXO on A549 potentiated the antiproliferative effect compared with DOXO treatment. After six days of treatment, dose and time-dependent effect of DOXO and TPN were observed. TPN showed inhibitory activity on p38-α (IC50 = 729 μM) and JAK3 (IC50 = 6.3 μM). After 48 h of treatment, necrosis was observed in cells treated with DOXO (21,5 %) and TPN (7,3 %). The co-treatment of both drugs increased the necrosis rate up to 33,5 %, as well in the 6th day of treatment (52,3 %). It was also observed a cell migration reduction after 120 h of TPN treatment in comparison with control. Based on that, TPN can be characterized as a potential biomolecule for new drugs development or even its use as adjuvant in the treatment of lung adenocarcinoma.
Cancer is one of the leading causes of death worldwide, with lung cancer as the major one. In Brazil, lung cancer is the second leading cause of cancer deaths in men (after the prostate cancer) and fourth in women. Rio Grande do Sul is the second Brazilian state with the highest incidence of cancer. Characterized by disordered cell growth, tumor development is defined by cell death evasion and has been closely correlated to inflammation. Standard cancer treatments, such as chemotherapy and radiotherapy, cause adverse effects on patients. Considering that most of the antineoplastic drugs produced are derived from natural compounds or their derivatives, natural products (especially those of plant origin) present potential in the search for new molecules for drug synthesis. Several phytoconstituents, such as the terpene α-terpineol (TPN), have antiproliferative and anticancer effects in cell lines of breast, prostate and ovary carcinomas, and leukemic cells. In the present study, the anti-proliferative potential of TPN on six human tumor cell lines (A549, MCF-7, HT-29, Caco-2, LNCaP and ACP-03) was evaluated. The A549 cell line (lung adenocarcinoma) was selected for experiments of six days with TPN and doxorubicin (DOXO) co-treatment. Mechanisms of cell death, molecular markers, enzymatic activity (JAK-3, JNK-3, p38-α), cell migration and inhibition of TNF-α were evaluated. Among the six lines, three of them (A549, MCF-7, HT-29) have shown a significant reduction of cell viability after 48 h treatment with TPN. Co-treatment of TPN and DOXO on A549 potentiated the antiproliferative effect compared with DOXO treatment. After six days of treatment, dose and time-dependent effect of DOXO and TPN were observed. TPN showed inhibitory activity on p38-α (IC50 = 729 μM) and JAK3 (IC50 = 6.3 μM). After 48 h of treatment, necrosis was observed in cells treated with DOXO (21,5 %) and TPN (7,3 %). The co-treatment of both drugs increased the necrosis rate up to 33,5 %, as well in the 6th day of treatment (52,3 %). It was also observed a cell migration reduction after 120 h of TPN treatment in comparison with control. Based on that, TPN can be characterized as a potential biomolecule for new drugs development or even its use as adjuvant in the treatment of lung adenocarcinoma.
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Palavras-chave
α-terpineol; A549; câncer; JAK3; p38-α
Citação
STOLL, Stefani Natali. Avaliação da atividade biológica de um terpeno em linhagem de câncer de pulmão de pequenas células (A549). 2017. Dissertação (Mestrado) – Curso de Biotecnologia, Universidade do Vale do Taquari - Univates, Lajeado, 11 dez. 2017. Disponível em: http://hdl.handle.net/10737/2012.