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Inhibition of Tumor Cell Invasion and Angiogenesis by Motuporamines¹

Departments of Anatomy [C. D. R., L. M. M.], Chemistry and Oceanography (EOS) [D. E. W., R. J. A.], and Biochemistry and Molecular Biology [L. M. M., M. R.], University of British Columbia, Vancouver, British Columbia V6T 1Z3; Departments of Pathology and Medical Biophysics, British Columbia Cancer Agency, Vancouver, British Columbia V5Z IL3 [K. G. L., A. K.]; and Jack Bell Research Laboratories, Vancouver, British Columbia V6H 3Z6 [A. T., S. D.], Canada

Tissue invasion is an important determinant of angiogenesis and metastasis and constitutes an attractive target for cancer therapy. We have developed an assay to identify agents that inhibit invasion by mechanisms other than inhibition of cell attachment or cytotoxicity. A screen of marine sponge extracts identified motuporamines as micromolar inhibitors of invasion of basement membrane gels by MDA-231 breast carcinoma, PC-3 prostate carcinoma, and U-87 and U-251 glioma cells. Motuporamine C inhibits cell migration in monolayer cultures and impairs actin-mediated membrane ruffling at the leading edge of lamellae. Motuporamine C also reduces ß1-integrin activation, raising the possibility that it interferes with "inside-out" signaling to integrins. In addition, motuporamine C inhibits angiogenesis in an in vitro sprouting assay with human endothelial cells and an in vivo chick chorioallantoic membrane assay. The motuporamines show little or no toxicity or inhibition of cell proliferation, and they are structurally simple and easy to synthesize, making them attractive drug candidates.

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