Roskelley C D, Williams D E, McHardy L M, Leong K G, Troussard A, Karsan A, Andersen R J, Dedhar S, Roberge M
Department of Anatomy, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Cancer Res. 2001 Sep 15;61(18):6788-94.
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 beta1-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.
组织侵袭是血管生成和转移的重要决定因素，也是癌症治疗的一个有吸引力的靶点。我们开发了一种检测方法，用于鉴定通过抑制细胞附着或细胞毒性以外的机制来抑制侵袭的药物。对海洋海绵提取物的筛选发现，莫图拉明是MDA - 231乳腺癌、PC - 3前列腺癌以及U - 87和U - 251胶质瘤细胞侵袭基底膜凝胶的微摩尔级抑制剂。莫图拉明C抑制单层培养中的细胞迁移，并损害肌动蛋白介导的片状伪足前缘的膜褶皱。莫图拉明C还降低β1整合素的活化，增加了其干扰整合素“由内向外”信号传导的可能性。此外，在用人内皮细胞进行的体外芽生试验和体内鸡胚绒毛尿囊膜试验中，莫图拉明C抑制血管生成。莫图拉明显示出很少或没有毒性，也不抑制细胞增殖，并且它们结构简单，易于合成，使其成为有吸引力的候选药物。
