ABSTRACT
This study investigated the mechanism by which fucoxanthin acts as a novel ferroptosis inducer to inhibit tongue cancer. The MTT assay was used to detect the inhibitory effects of fucoxanthin on SCC-25 human tongue squamous carcinoma cells. The levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and total iron were measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to assess glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (Nrf2), Keap1, solute carrier family 7 member 11 (SLC7A11), transferrin receptor protein 1 (TFR1), p53, and heme oxygenase 1 (HO-1) expression. Molecular docking was performed to validate interactions. Compared with the control group, the activity of fucoxanthin-treated SCC-25 cells significantly decreased in a dose- and time-dependent manner. The levels of MMP, GSH, and SOD significantly decreased in fucoxanthin-treated SCC-25 cells; the levels of ROS, MDA, and total iron significantly increased. mRNA and protein expression levels of Keap1, GPX4, Nrf2, and HO-1 in fucoxanthin-treated cells were significantly decreased, whereas levels of TFR1 and p53 were significantly increased, in a concentration-dependent manner. Molecular docking analysis revealed that binding free energies of fucoxanthin with p53, SLC7A11, GPX4, Nrf2, Keap1, HO-1, and TFR1 were below -5 kcal/mol, primarily based on active site hydrogen bonding. Our findings suggest that fucoxanthin can induce ferroptosis in SCC-25 cells, highlighting its potential as a treatment for tongue cancer.
Subject(s)
Ferroptosis , Heme Oxygenase-1 , Molecular Docking Simulation , NF-E2-Related Factor 2 , Phospholipid Hydroperoxide Glutathione Peroxidase , Xanthophylls , Humans , NF-E2-Related Factor 2/metabolism , Ferroptosis/drug effects , Xanthophylls/pharmacology , Xanthophylls/chemistry , Heme Oxygenase-1/metabolism , Heme Oxygenase-1/genetics , Cell Line, Tumor , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Tongue Neoplasms/drug therapy , Tongue Neoplasms/metabolism , Tongue Neoplasms/pathology , Receptors, Transferrin/metabolism , Membrane Potential, Mitochondrial/drug effects , Kelch-Like ECH-Associated Protein 1/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Amino Acid Transport System y+/metabolism , Amino Acid Transport System y+/genetics , Superoxide Dismutase/metabolism , Down-Regulation/drug effects , Antigens, CDABSTRACT
Human pharyngeal squamous cell carcinoma (HPSCC) is the most common malignancy in the head and neck region, characterized by high mortality and a propensity for metastasis. Fucoxanthin, a carotenoid isolated from brown algae, exhibits pharmacological properties associated with the suppression of tumor proliferation and metastasis. Nevertheless, its potential to inhibit HPSCC proliferation and metastasis has not been fully elucidated. This study represents the first exploration of the inhibitory effects of fucoxanthin on two human pharyngeal squamous carcinoma cell lines (FaDu and Detroit 562), as well as the mechanisms underlying those effects. The results showed dose-dependent decreases in the proliferation, migration, and invasion of HPSCC cells after fucoxanthin treatment. Further studies indicated that fucoxanthin caused a significant reduction in the expression levels of proteins in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, as well as the downstream proteins matrix metalloproteinase (MMP)-2 and MMP-9. Specific activators of PI3K/AKT reversed the effects of fucoxanthin on these proteins, as well as on cell proliferation and metastasis, in FaDu and Detroit 562 cells. Molecular docking assays confirmed that fucoxanthin strongly interacted with PI3K, AKT, mTOR, MMP-2, and MMP-9. Overall, fucoxanthin, a functional food component, is a potential therapeutic agent for HPSCC.
Subject(s)
Cell Movement , Cell Proliferation , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Signal Transduction , TOR Serine-Threonine Kinases , Xanthophylls , Humans , TOR Serine-Threonine Kinases/metabolism , Xanthophylls/pharmacology , Xanthophylls/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Cell Proliferation/drug effects , Signal Transduction/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Pharyngeal Neoplasms/drug therapy , Pharyngeal Neoplasms/pathology , Pharyngeal Neoplasms/metabolism , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Neoplasm Metastasis , Molecular Docking SimulationABSTRACT
OBJECTIVE: To observe the pharmacokinetics of adriamycin-adsorbing nanometric activated carbon in intralymphatic chemotherapy. METHODS: Two ml of suspension of activated carbon with the diameter of 21 nm was mixed with adriamycin 5 mg. Eighteen dogs were randomly divided into 6 equal groups. The above mentioned mixture was injected subserosally to the anterior wall of gastric antrum of the dogs. Thirty minutes, 1 h, 2 h, 1 day, and 3 days after the injection the gastroepiploic lymph nodes of the Groups 1 - 5 were obtained. And Group 6 underwent extraction of venous blood samples 5, 15, 30, 60, 120, and 240 minutes after the injection and extraction of thoracic duct fluid 5, 15, 30, 60, 120, 240, and 360 minutes after the injection. The adriamycin concentrations at different time points were determined by mass spectrometer. The lymphatic vessels and nodes at the gastric wall were observed by the naked eyes. RESULTS: Black tiny lymphatic vessels and lymph nodes were visualized around the injection areas immediately after the injection. Adriamycin content could be detected 30 min after the injection and lasted for 72 h at high levels with the peak content of (84.6 +/- 2.0) microg per gram tissue at 60 min in the perilymph node of gastroepiploic artery. The adriamycin concentration in the lymph fluid of thoracic duct reached the top level of 162.5 ng/ml 30 min after the injection, and then decreased slowly. Adriamycin could be still detected in lymph fluid 6 h after injection. No trace of adriamycin was found in the blood at any time points. CONCLUSION: The content of adriamycin can keep high and last long in the drainage of lymph node and lymph fluid in the treatment of intralymphatic chemotherapy using adriamycin-adsorbing nanometric activated carbon.