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Research Articles: Therapeutics, Targets, and Development

Agelastatin A: a novel inhibitor of osteopontin-mediated adhesion, invasion, and colony formation

¹ Centre for Cancer Research and Cell Biology and ² The School of Chemistry and Chemical Engineering, Queen's University Belfast, Belfast, Northern Ireland and ³ The Chemistry Department, University College London, London, United Kingdom

Requests for reprints: Mohamed El-Tanani, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland. Phone: 442-890-972-789; Fax: 442-890-972-776. E-mail: m.el-tanani{at}qub.ac.uk

Abstract

Effective inhibitors of osteopontin (OPN)–mediated neoplastic transformation and metastasis are still lacking. (-)-Agelastatin A is a naturally occurring oroidin alkaloid with powerful antitumor effects that, in many cases, are superior to cisplatin in vitro. In this regard, past comparative assaying of the two agents against a range of human tumor cell lines has revealed that typically (-)-agelastatin A is 1.5 to 16 times more potent than cisplatin at inhibiting cell growth, its effects being most pronounced against human bladder, skin, colon, and breast carcinomas. In this study, we have investigated the effects of (-)-agelastatin A on OPN-mediated malignant transformation using mammary epithelial cell lines. Treatment with (-)-agelastatin A inhibited OPN protein expression and enhanced expression of the cellular OPN inhibitor, Tcf-4. (-)-Agelastatin A treatment also reduced β-catenin protein expression and reduced anchorage-independent growth, adhesion, and invasion in R37 OPN pBK-CMV and C9 cell lines. Similar effects were observed in MDA-MB-231 and MDA-MB-435s human breast cancer cell lines exposed to (-)-agelastatin A. Suppression of Tcf-4 by RNA interference (short interfering RNA) induced malignant/invasive transformation in parental benign Rama 37 cells; significantly, these events were reversed by treatment with (-)-agelastatin A. Our study reveals, for the very first time, that (-)-agelastatin A down-regulates β-catenin expression while simultaneously up-regulating Tcf-4 and that these combined effects cause repression of OPN and inhibition of OPN-mediated malignant cell invasion, adhesion, and colony formation in vitro. We have also shown that (-)-agelastatin A inhibits cancer cell proliferation by causing cells to accumulate in the G₂ phase of cell cycle. [Mol Cancer Ther 2008;7(3):548–58]

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Note: C.K. Mason and S. McFarlane contributed equally to this work.

Received 11/ 1/07; accepted 12/19/07.