title: Celastrol induced DNA damage, cell cycle arrest, and apoptosis in human rheumatoid fibroblast-like synovial cells.
abstract: Celastrol is one of the principal active ingredients of Tripterygium wilfordii Hook.f., a toxic Chinese medical herb traditionally prescribed for controlling pain and inhibiting inflammation in various chronic inflammatory diseases, including rheumatoid arthritis (RA). Resistance to apoptosis of fibroblast-like synoviocytes is considered a major characteristic of RA. In this study, we test celastrol's cytotoxic effect and potential mechanisms in human rheumatoid synovial fibroblasts (RA-FLS). In the cytotoxic assay, we found that celastrol dose-dependently decreased RA-FLS viability and increased LDH release. The apoptotic nuclear morphology was observed after celastrol treatment as determined by DAPI fluorescence staining. Flow cytometry analysis with PI and Annexin V revealed that celastrol induced RA-FLS cell cycle arrest in the G2/M phase and apoptosis. Furthermore, celastrol dramatically increased expression of Bax/Bcl-2, proteolytic cleavage of Caspase-3, -9, PARP, and decreased expression of FasR. In addition, celastrol treatment resulted in DNA damage. Collectively, we concluded that celastrol inhibits RA-FLS proliferation by inducing DNA damage, cell cycle arrest, and apoptosis in vitro, which might provide data for its application in RA treatment.
authors.affiliation: Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
authors.forename: Zengtao
authors.initials: Z
authors.lastname: Xu
authors.forename: Guosheng
authors.initials: G
authors.lastname: Wu
authors.forename: Xu
authors.initials: X
authors.lastname: Wei
authors.forename: Xiuping
authors.initials: X
authors.lastname: Chen
authors.forename: Yitao
authors.initials: Y
authors.lastname: Wang
authors.forename: Lidian
authors.initials: L
authors.lastname: Chen
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053978:Pentacyclic Triterpenes; D008517:Phytotherapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects*; D029757:Tripterygium / Q000737:chemistry*; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D004365:Drugs, Chinese Herbal; D053978:Pentacyclic Triterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; D014315:Triterpenes; D051028:bcl-2-Associated X Protein; D020169:Caspases; C050414:celastrol