A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity.
Androgen deprivation therapy causes a paradoxical elevation of matrix metalloproteinases (MMPs) including MMP-9 resulting in aggressive tumor phenotype in many patients with prostate cancer. In this study, we have evaluated a novel antisense phosphorodiamidate Morpholino oligomer (PMO) targeted against MMP-9 in models of angiogenesis and in human prostate xenograft in athymic mice. The treatment of androgen-independent DU145 human prostate cells with a 21-mer MMP-9 antisense PMO caused a dose-dependent inhibition of cell proliferation compared to scrambled or MMP-2 antisense PMO at similar concentrations. This was associated with decreases in MMP-9 expression, gelatinolytic activity and increased stability of the insulin-like growth factor-binding protein (IGFBP-3), a proapoptotic factor and MMP-9 substrate. In vitro invasion assays revealed a 40-60% inhibition of DU145 cell invasion in the presence of 25 microM MMP-9 antisense PMO. A significant decrease in endothelial cell migration and vascularization was observed in the Matrigel plug assay in mice when treated intraperitoneally with 300 microg/day MMP-9 antisense for 21 days. In the highly vascular DU145 tumor xenografts, MMP-9 inhibition caused decreased tumor growth with regression in 50% of the animals. Histological analysis revealed increased apoptosis and fibrous tissue deposits in the MMP-9 antisense-treated tumors compared to the scrambled and saline controls. No apparent toxicity or mortality was associated with the MMP-9 PMO treatment. In summary, the MMP-9 antisense PMO inhibited in vitro prostate cancer cell proliferation, invasion and in vivo angiogenesis. These data establish the feasibility of developing a site-directed, nontoxic antisense therapeutic agent for inhibiting local invasion and metastasis.
London
Carla A
CA
AVI BioPharma Inc., 4575 SW Research Way, Suite 200, Corvallis, Oregon 97333, USA.
Sekhon
Harmanjatinder S
HS
Arora
Vikram
V
Stein
David A
DA
Iversen
Patrick L
PL
Devi
Gayathri R
GR
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D015197:Carcinogenicity Tests; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011467:Prostate / Q000098:blood supply / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D018972:Insulin-Like Growth Factor Binding Protein 3; D061965:Matrix Metalloproteinase Inhibitors; D016376:Oligonucleotides, Antisense; D020780:Matrix Metalloproteinase 9