Imatinib mesylate induces mitochondria-dependent apoptosis and inhibits invasion of human pigmented villonodular synovitis fibroblast-like synovial cells.
Pigmented villonodular synovitis (PVNS) is a rare sarcoma-like disorder characterized by synovial lesions proliferation and invasion to articular cartilage for which no effective treatments are available. Imatinib mesylate (IM) is known to exert antitumor activity in some tumors, but its effects on PVNS fibroblast-like synoviocytes (PVNS-FLS) and the specific mechanism involved remain to be established. In the present study, the in vitro effects of IM on cell proliferation and survival rates were investigated in PVNS-FLS. Apoptosis induction was assessed via acridine orange/ethidium bromide (AO)/(EB) and Annexin V/PI staining as well as western blotting. The invasion ability of PVNS-FLS was evaluated by Transwell invasion chambers. IM significantly inhibited survival and invasion ability of PVNS-FLS in a dose- and time-dependent manner. The drug-treated cell groups exhibited markedly higher apoptosis, which was blocked upon pretreatment with the specific caspase-9 inhibitor Z-LEHD-FMK. Expression of cleaved caspase-9 was significantly increased and the Bcl-2 family and caspase-3 were activated following treatment with IM. Our results collectively demonstrated that IM has a strong antiproliferative effect on PVNS-FLS in vitro, attributable to induction of mitochondrial-dependent apoptosis in association with activation of caspase-9/-3 and the Bcl-2/Bax family, and exhibits significant inhibition on the invasion ability of PVNS-FLS, suggesting that IM may be useful as a novel treatment of this disease.
Department of Orthopedics, The First Affiliated Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
Kang
K
Chen
Department of Medicine, Benxi Central Hospital, Benxi, Liaoning 117000, P.R. China.
Qiao
Q
Ren
Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
Xiao-Rui
XR
Han
Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
Xiao-Nan
XN
Zhang
Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
Bo
B
Wei
Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.
Xi-Zhuang
XZ
Bai
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D013586:Synovitis, Pigmented Villonodular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9