A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity
A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity
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DOI：
10.1038/sj.cgt.7700642
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发表时间：
2003-11-01
影响因子：
6.4
通讯作者：
Devi, GR
中科院分区：
文献类型：
--
作者：
London, CA;Sekhon, HS;Devi, GR
雄激素剥夺治疗导致基质金属蛋白酶（MMPs）（包括MMP-9）的反常升高，导致许多前列腺癌患者的侵袭性肿瘤表型。在这项研究中，我们已经评估了一种新的反义磷酰二胺吗啉寡聚体（PMO）针对MMP-9的血管生成模型和人前列腺裸鼠移植瘤。雄激素非依赖性DU 145人前列腺细胞与21聚体MMP-9反义PMO的治疗引起的细胞增殖的剂量依赖性抑制相比，乱序或MMP-2反义PMO在相似的浓度。这与MMP-9表达减少、明胶分解活性和胰岛素样生长因子结合蛋白（IGFBP-3）（一种促凋亡因子和MMP-9底物）稳定性增加有关。体外侵袭实验显示，在25 μ M MMP-9反义PMO存在下，DU 145细胞的侵袭抑制率为40-60%。当用300 μ g/天MMP-9反义物腹膜内处理小鼠21天时，在基质胶塞测定中观察到内皮细胞迁移和血管形成的显著减少。在高度血管化的DU 145肿瘤异种移植物中，MMP-9抑制导致肿瘤生长减少，50%的动物肿瘤消退。组织学分析显示，MMP-9反义治疗的肿瘤细胞凋亡和纤维组织沉积增加相比，乱和盐水对照。没有明显的毒性或死亡率与MMP-9 PMO治疗相关。总之，MMP-9反义PMO抑制体外前列腺癌细胞增殖、侵袭和体内血管生成。这些数据确立了开发用于抑制局部侵袭和转移的定点、无毒反义治疗剂的可行性。
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 muM 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 mug/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.