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Depsipeptide inhibits migration of primary and metastatic uveal melanoma cell lines in vitro: a potential strategy for uveal melanoma

Klisovic, Dino D.a; Klisovic, Marko I.b; Effron, Davidc; Liu, Shujunb; Marcucci, Guidob; Katz, Steven E.a

ORIGINAL ARTICLES
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Uveal melanoma (UM) is a highly malignant primary intraocular tumour in adults that has a high mortality rate due to haematogenous dissemination. The migration of UM cells through the basement membrane requires the presence of proteolytic enzymes, such as matrix metalloproteinases (MMPs). The expression of MMP-2, MMP-9 and membrane type-1/MMP (MT-1/MMP) in UM cells is a known risk factor for metastatic disease. We tested the effect of depsipeptide (DP) on UM cell migration and the level and activity of MMP-2, MMP-9, MT-1/MMP and tissue inhibitors of matrix metalloproteinases 1 and 2 (TIMP-1 and TIMP-2). Three primary and two metastatic (liver metastasis) UM cell lines were treated with DP (0, 1, 5 and 10 nmol/l) for 24 h. Migration of UM cells was studied in modified Boyden migration chambers for 24 h and only viable cells on both sides of the membrane were counted. Enzyme-linked immunosorbent assays (ELISAs) were used to quantify the level of MMP-2, MMP-9, MT-1/MMP, TIMP-1 and TIMP-2 after the cells had been exposed to DP (0, 1, 5 and 10 nmol/l) for 24 h. In addition, the activities of MMP-2, MMP-9 and MT-1/MMP were determined after DP treatment. A dose-dependent decrease in the migration of viable UM cells was observed for primary and metastatic cell lines (30–50% inhibition). We detected a dose-dependent: (1) decrease in the protein level of MMP-2, MMP-9 and MT-1/MMP; (2) decrease in the activity of MMP-2, MMP-9 and MT-1/MMP; and (3) increase in the protein level of TIMP-1 and TIMP-2. It can be concluded that DP is a potent inhibitor of primary and metastatic UM cell migration in vitro. Our data suggest that this inhibition is mediated by the downregulation of MMPs and the upregulation of TIMPs. DP may be a valuable adjunctive treatment modality for primary and metastatic UM in humans.

aWilliam H. Havener Eye Center

bDepartment of Internal Medicine, Division of Hematology and Oncology, The Ohio State University, Columbus, OH, USA

cWexner Institute for Pediatric Research, Children's Hospital, Columbus, OH, USA

Sponsorship: This study was supported in part by the Ohio Lions Eye Research Foundation and The Carl M. and Grace C. Baldwin Eye Care Fund.

Correspondence and requests for reprints to Dr Dino D. Klisovic, Department of Ophthalmology, Tulane University, 1430 Tulane Avenue, SL-69, 5th Floor, New Orleans, LA 70112-2699, USA

Tel: 504-988-5314; fax: 504-584-2684;

e-mail: dklisovic@cox.net

Received 11 May 2004 Accepted (after revision) 17 February 2005

© 2005 Lippincott Williams & Wilkins, Inc.