RESUMO
Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive system, and Chinese herbal medicine plays an important role in tumor treatment. The in-depth study of auriculasin isolated from Flemingia philippinensis showed that auriculasin promoted reactive oxygen species (ROS) generation in a concentration-dependent manner; when ROS scavenger NAC was added, the effects of auriculasin in promoting ROS generation and inhibiting cell viability were blocked. Auriculasin induced CRC cell apoptosis, led to mitochondrial shrinkage, and increased the intracellular accumulation of Fe2+ and MDA. When auriculasin and NAC were added simultaneously, the levels of apoptosis, Fe2+ and MDA returned to the control group levels, indicating that auriculasin activated apoptosis and ferroptosis by inducing ROS generation. In addition, auriculasin promoted the expression of Keap1 and AIFM1, but significantly reduced the phosphorylation level of AIFM1, while NAC significantly blocked the regulation of Keap1 and AIFM1 by auriculasin, which indicates that auriculasin can also induce oxeiptosis through ROS. When Z-VAD-FMK, Ferrostatin-1, Keap1 siRNA, PGAM5 siRNA and AIFM1 siRNA were added respectively, the inhibitory effect of auriculasin on cell viability was significantly weakened, indicating that auriculasin inhibits cell viability by inducing apoptosis, ferroptosis and oxeiptosis. Auriculasin also inhibited the invasion and clone forming ability of CRC cells, while NAC blocked the above effects of auriculasin. Therefore, auriculasin can promote CRC cell apoptosis, ferroptosis and oxeiptosis by inducing ROS generation, thereby inhibiting cell viability, invasion and clone formation, indicating that auriculasin has a significant antitumor effect.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Isoflavonas/farmacologia , Espécies Reativas de Oxigênio/agonistas , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/genética , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Fabaceae/química , Ferroptose/genética , Células HCT116 , Humanos , Ferro/agonistas , Ferro/metabolismo , Isoflavonas/isolamento & purificação , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Malondialdeído/agonistas , Malondialdeído/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Plectranthus barbatus Andrews (Lamiaceae) é uma planta muita utilizada na medicina popular para o tratamento de doenças gastrointestinais e hepáticas. O objetivo do presente trabalho foi estudar o efeito protetor do extrato aquoso de P. barbatus (EAPB) sobre os danos hepáticos causados pela sobrecarga de ferro provocada pelo ferro-dextran em ratos. O tratamento com ferro-dextran induziu uma redução significativa na concentração de glutationa reduzida nos animais tratados em relação ao grupo controle e o tratamento prévio dos animais com o EAPB protegeu o fígado do efeito provocado pelo ferro neste parâmetro. Com relação à lipoperoxidação, houve aumento significativo na concentração de malondialdeído (MDA) nos animais tratados em relação ao controle, entretanto, quando os animais receberam o tratamento prévio com o EAPB, houve redução significativa na concentração do MDA. A análise histopatológica mostrou que o grupo tratado com ferro-dextran apresentou grânulos de ferro no citoplasma das células de Kupffer com alargamento das mesmas e algumas com os núcleos hipertróficos. O tratamento prévio com EAPB resultou no desaparecimento dos sinais de danos às células de Kupffer sem nenhum núcleo hipertrófico, mas com a presença de grânulos de ferro totalmente fagocitados, o que demonstra uma aparência morfológica normal. Portanto, o EAPB pode ser útil na prevenção de danos hepáticos induzidos por sobrecarga de ferro.
The Plectranthus barbatus Andrews (Lamiaceae) is a plant largely used in folk medicine to treat gastrointestinal and liver diseases. The objective of this work was to study the protective effect of the aqueous extract of P. barbatus (EAPB) against damage caused by iron overload induced by iron dextran in rat liver. Treatment with iron-dextran induced a significant reduction in the glutathione levels in treated animals compared to control group, and the pretreatment of animals with EAPB protected the liver from the effects caused by iron in this parameter. With respect to lipid peroxidation, a significant increase in the malondialdehyde (MDA) levels in treated animals compared to control was observed; however, when the animals were pretreated with EAPB, there was a significant reduction in the MDA levels. Histopathological analysis showed that the group treated with iron-dextran showed iron granules in the cytoplasm of the Kupffer cells and some of them presented enlarged nuclei. The group previously treated with EAPB showed the disappearance of the signs of damage to the Kupffer cells with no nucleus hypertrophy but with the presence of iron granules completely phagocytosed by these cells, which showed a normal morphological appearance. Therefore, the EAPB may be useful in the prevention of liver damage induced by iron overload.