RESUMO
Placental extract contains several biologically active compounds, and pharmacological induction of placental extract has therapeutic effects, such as improving liver function in patients with hepatitis or cirrhosis. Here, we searched for novel molecules with an anti-tumor activity in placental extracts. Active molecules were separated by chromatographic analysis, and their antiproliferative activities were determined by a colorimetric assay. We identified aspartic acid and glutamic acid to possess the antiproliferative activity against human hepatoma cells. Furthermore, we showed that the combination of aspartic acid and glutamic acid exhibited enhanced antiproliferative activity, and inhibited Akt phosphorylation. We also examined in vivo tumor inhibition activity using the rabbit VX2 liver tumor model. The treatment mixture (emulsion of the amino acids with Lipiodol) administered by hepatic artery injection inhibited tumor cell growth of the rabbit VX2 liver. These results suggest that the combination of aspartic acid and glutamic acid may be useful for induction of tumor cell death, and has the potential for clinical use as a cancer therapeutic agent.
Assuntos
Ácido Aspártico/farmacologia , Ácido Glutâmico/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Placenta/química , Placenta/metabolismo , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Coelhos , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We purified pyroglutamic acid from human placental extract and identified it as a potent stimulator of rat primary hepatocyte DNA synthesis. Pyroglutamic acid dose-dependently stimulated DNA synthesis, and this effect was inhibited by PD98059, a dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1) inhibitor. Therefore, pyroglutamic acid stimulated DNA synthesis in rat primary hepatocytes via MAPK signaling.
Assuntos
DNA/biossíntese , Hepatócitos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ácido Pirrolidonocarboxílico/farmacologia , Animais , Células Cultivadas , Cromatografia Líquida/métodos , DNA/efeitos dos fármacos , Feminino , Flavonoides/farmacologia , Hepatócitos/fisiologia , Humanos , Imidazóis/farmacologia , Masculino , Espectrometria de Massas/métodos , Placenta/química , Gravidez , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Ácido Pirrolidonocarboxílico/isolamento & purificação , Ratos Sprague-DawleyRESUMO
BACKGROUND: Three-dimensional (3D) in vitro cultures can recapitulate the physiological in vivo microenvironment. 3D Modeling techniques have been investigated and applied in anticancer drug screening. MATERIALS AND METHODS: A silicate fiber scaffold was used for 3D cell cultures, and used to model the efficacy of anticancer drugs, such as mytomicin C and doxorubicin. RESULTS: A unique 3D structure was observed in 13 human tumor cell lines on scaffold, and these cells exhibited higher drug resistance than cells in two-dimensional (2D) cultures. Furthermore, the production of lactate and expression of the nuclear factor-kappa B (NF-κB)-regulated genes B cell lymphoma-2 (BCL2), cyclooxygenase-2 (COX2), and vascular endothelial growth factor (VEGF) were higher in 3D cultures than in 2D cultures. CONCLUSION: These findings suggest that a 3D model using a silicate fiber scaffold can mimic features of cancer, and is also a suitable model for the evaluation of anticancer drugs in vitro.
