cyclin-d1 and ellipticine

Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is an alkaloid isolated from Apocyanaceae plants. This study was designed to investigate the effects of ellipticine on the proliferation and apoptosis of fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA).. RA-FLSs were exposed to different concentrations of ellipticine (i.e., 0.5, 1, 2, 4 and 8 μM) for 24-72h and measured for viability, proliferation and apoptosis. The involvement of signal transducer and activators of transcription 3 (STAT3) signaling in the action of ellipticine was determined by Western blot analysis, luciferase reporter assay and rescue experiments.. Ellipticine treatment significantly inhibited the viability and proliferation of RA-FLSs in a concentration-dependent manner. In contrast, ellipticine exposure did not alter the viability of normal human FLSs. Moreover, ellipticine triggered significant apoptosis and increased caspase-3 activity in RA-FLSs. Mechanistically, ellipticine reduced the phosphorylation of STAT3 and downregulated the expression of Mcl-1, cyclin D1 and Bcl-2. Luciferase reporter assay demonstrated that ellipticine treatment led to a significant inhibition of STAT3-mediated transcriptional activity in RA-FLSs. Overexpression of constitutively active STAT3 reversed the suppressive effects of ellipticine on RA-FLSs, which was accompanied by restoration of Mcl-1, cyclin D1 and Bcl-2.. Ellipticine shows anti-proliferative and pro-apoptotic effects on RA-FLSs through inhibition of the STAT3 pathway and may have therapeutic potential in RA.

Topics: Apoptosis; Arthritis, Rheumatoid; Caspase 3; Cell Proliferation; Cells, Cultured; Cyclin D1; Down-Regulation; Ellipticines; Fibroblasts; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; STAT3 Transcription Factor; Synovial Membrane; Synoviocytes; Transcription, Genetic