AIMTo investigate the effect of DAPT (gamma-secretase inhibitor) on the growth of human tongue carcinoma cells and to determine the molecular mechanism to enable the potential application of DAPT to the treatment of tongue carcinoma.

METHODOLOGYHuman tongue carcinoma Tca8113 cells were cultured with DAPT. Cell growth was determined using Indigotic Reduction method. The cell cycle and apoptosis were analyzed by flow cytometry. Real-time PCR and Immuno-Fluorescence (IF) were employed to determine the intracellular expression levels.

RESULTSDAPT inhibited the growth of human tongue carcinoma Tca8113 cells by inducing G0-G1 cell cycle arrest and apoptosis. The mRNA levels of Hairy/Enhancer of Split-1 (Hes-1), a target of Notch activation, were reduced by DAPT in a dose-dependent manner. Coincident with this observation, DAPT induced a dose-dependent promotion of constitutive Caspase-3 in Tca8113 cells.

CONCLUSIONDAPT may have a therapeutic value for human tongue carcinoma. Moreover, the effects of DAPT in tumor inhibition may arise partly via the modulation of Notch-1 and Caspase-3.

Amyloid Precursor Protein Secretases ; antagonists & inhibitors ; Antineoplastic Agents ; administration & dosage ; pharmacology ; Apoptosis ; drug effects ; Basic Helix-Loop-Helix Transcription Factors ; drug effects ; Carcinoma ; pathology ; Caspase 3 ; drug effects ; Cell Line, Tumor ; Cell Membrane ; drug effects ; Cell Nucleus ; drug effects ; Cyclin D1 ; drug effects ; Dipeptides ; administration & dosage ; pharmacology ; Dose-Response Relationship, Drug ; G1 Phase ; drug effects ; Homeodomain Proteins ; drug effects ; Humans ; Receptor, Notch1 ; drug effects ; Repressor Proteins ; drug effects ; Resting Phase, Cell Cycle ; drug effects ; Tongue Neoplasms ; pathology ; Transcription Factor HES-1

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.
Humans ; CTLA-4 Antigen ; Immune Checkpoint Inhibitors/therapeutic use* ; Liver ; Prospective Studies ; Skin Neoplasms