Inhibition of tumor cell invasion and angiogenesis by motuporamines.
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.
Roskelley
C D
CD
Department of Anatomy, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Williams
D E
DE
McHardy
L M
LM
Leong
K G
KG
Troussard
A
A
Karsan
A
A
Andersen
R J
RJ
Dedhar
S
S
Roberge
M
M
D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011161:Porifera / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000970:Antineoplastic Agents; D019012:Integrin beta1; C409085:motuporamine C