RESUMO
Breast cancer is the most common malignancy in women all around the world, especially in many countries in Asia. However, antitumor drugs with unique curative effects and low toxic side-effects have not been found yet. Warangalone is an isoflavone extracted from the Cudrania tricuspidata fruit, and is reported to possess anti-inflammatory and anti-cancer activity. The purpose of this study was to determine the effects of warangalone on breast cancer cells. In this study, we found that warangalone decreased the viability of breast cancer cells by increasing the generation of reactive oxygen species (ROS) resulting in mitochondrial damage and decreased mitochondrial membrane potential (MMP). Warangalone induced mitochondrial apoptosis by increasing the BAX/BCL-2 ratio. Warangalone activated mitophagy via upregulation of PINK1 and Parkin expression and co-localization. The combination of warangalone and autophagy inhibitors or PINK1 siRNA increased the degree of cell apoptosis compared to treatment with warangalone alone. Warangalone damages mitochondria via ROS, thereby triggering PINK1/Parkin-mediated mitophagy and inducing mitochondrial apoptosis. However, autophagy/mitophagy protects against warangalone-induced mitochondrial apoptosis. A combination of warangalone and autophagy/mitophagy inhibitors may be a potential treatment for breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Isoflavonas/farmacologia , Mitofagia/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoflavonas/uso terapêutico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mitofagia/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
OBJECTIVE: To prepare warangalone-loaded thermosensitive liposomes (WLTSL) and evaluate its inhibitory effect on breast cancer cells in vitro. METHODS: MTT assay was used to assess the changes in proliferation of 3 breast cancer cell lines (MDA-MB-231, MCF7, and SKBR3) following treatment with warangalone, soy isoflavone and genistein. Colony-forming assay and wound healing assay was used to assess colony forming activity and migration of MDA-MB-231 cells treated with warangalone. The effect of warangalone on the expression of MMP2 and MMP9 in MDA-MB-231 cells was examined with Western blotting. The thermosensitive liposomes (TSL) and WLTSL were prepared using a thin film hydration method, and the morphology, size, encapsulation efficiency and stability of the prepared liposomes were characterized using transmission electron microscopy, dynamic light scattering scanning and UV spectrophotometry. MTT assay was used to examine the inhibitory effect of WLTSL on mouse breast cancer cells (4T1) in vitro. RESULTS: Warangalone showed stronger anti-proliferation effects than soy isoflavones and genistein in the 3 human breast cancer cell lines and significantly inhibited colony formation by MDA-MB-231 cells. Treatment with warangalone significantly inhibited migration of the breast cancer cells and down-regulated the cellular expressions of MMP2 and MMP9. The prepared TSL and WLTSL presented with a homogeneous, irregular spherical morphology, with a mean particle size of 56.23±0.61 nm, a polymer dispersity index of 0.241±0.014, a Zeta potential of -40.40±0.46 mV, and an encapsulation efficiency was 87.68±2.41%. WLTSL showed a good stability at 4 â and 37 â and a stronger inhibitory effect than warangalone in 4T1 cells. CONCLUSIONS: Warangalone inhibits the proliferation, migration and invasion of breast cancer cells, and the prepared WLTSL possesses good physical properties and strong anti-breast cancer activity.
Assuntos
Neoplasias da Mama , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Isoflavonas , Lipossomos , CamundongosRESUMO
Scandenolone, an isoflavone, has shown anti-cancer potential. In this study, we extracted scandenolone from Cudrania tricuspidata fruit and evaluated its anti-breast cancer effects as well as toxicity in cell and animal models. In cell model, scandenolone suppressed the breast cancer MCF-7â¯cells viability, ceased mitotic cell cycle, decreased mitochondrial membrane potential, up-regulated cleaved caspase-3 and promoted the phosphorylation of p53. Additionally, this isoflavone promoted cell apoptosis and induced a sustained activation of the phosphorylation of p38 and ERK, but not JNK and Akt. The effects were further verified in a human MCF-7 breast cancer xenograft model, where scandenolone efficiently suppressed the cancer growth and increased apoptotic cells in tumor tissue. However scandenolone has also shown certain toxicity to normal hepatocytes and breast epithelial cells. It could be concluded that scandenolone suppressed the growth of breast cancer cells, but its toxicity towards normal cells might limit its potential clinical use.