2004
DOI: 10.1073/pnas.0404105101
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Abstract: The hallmark of rheumatoid arthritis (RA) is the progressive destruction of articular joints, characterized by invasive synovial hyperplasia and pathological neovascularization. Here we report that PPI-2458, a member of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibits the proliferation of human fibroblast-like synoviocytes (HFLS-RA), derived from RA patients, with a growth inhibitory concentration 50 (GI 50) of 0.04 nM and a maximum inhibition of >95% at … Show more

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Cited by 99 publications
(134 citation statements)
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“…Although proliferation was not completely inhibited even at the highest concentration of PPI-2458, the degree of inhibition was substantial at low-nanomolar concentrations of PPI-2458 provided as single doses at the start of the experiment. Further, growth inhibition was reversible as removal of drug from cultures resulted in resumption of exponential growth similar to that of untreated cells (data not shown); data are consistent with prior observations made with human fibroblast-like synoviocytes from RA patients (26).…”
Section: Resultssupporting
confidence: 89%
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“…Although proliferation was not completely inhibited even at the highest concentration of PPI-2458, the degree of inhibition was substantial at low-nanomolar concentrations of PPI-2458 provided as single doses at the start of the experiment. Further, growth inhibition was reversible as removal of drug from cultures resulted in resumption of exponential growth similar to that of untreated cells (data not shown); data are consistent with prior observations made with human fibroblast-like synoviocytes from RA patients (26).…”
Section: Resultssupporting
confidence: 89%
“…In cell systems, PPI-2458 was shown to deplete free, active MetAP-2 and inhibit endothelial cell proliferation in a coordinated, concentrationdependent manner, thereby suggesting a causal relationship between MetAP-2 enzyme inhibition and endothelial growth inhibition (26,27). Furthermore, the dependence of PPI-2458 activity on the expression of MetAP-2 was confirmed as depletion of MetAP-2 by small interfering RNA rendered cells refractory to further growth inhibition by PPI-2458 (27).…”
Section: Discussionmentioning
confidence: 89%
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“…It is noteworthy that PPI-2458, a member of the fumagillin class of compounds, potently inhibits the proliferation of human fibroblast-like synoviocytes derived from rheumatoid arthritis patients and displays a significant in vivo activity in a rat model of rheumatoid arthritis. This feature supports the potential application of PPI-2458 as a drug for the treatment of rheumatoid arthritis, disorder in which an induced co-expression of Ets-1 and Stromelysin-1 is observed linked to a pathological neovascularization (Bernier et al, 2004). The induction of various MMPs is dependent on MAP kinase activation and Ets factors .…”
Section: Stromelysin-1 Promoter Regulation By Endogenous Ets-1 D Bailsupporting
confidence: 73%
“…Sustained inhibition of angiogenesis that is begun during the induction, or at the onset, of synovitis can reduce inflammation and joint damage (21,23,27,37,38). However, adverse effects of long-term angiogenesis inhibition on physiologic blood vessel growth may outweigh the therapeutic benefit in chronic inflammatory diseases.…”
Section: Discussionmentioning
confidence: 99%