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.