Human malignant glioma therapy using anti-alpha(v)beta3 integrin agents.
Human malignant glioma therapy using anti-alpha(v)beta3 integrin agents.
复制标题
使用抗α(v)β3整合素药物治疗人类恶性神经胶质瘤。
DOI：
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发表时间：
2000
影响因子：
3.9
通讯作者：
G. Gillespie
中科院分区：
文献类型：
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作者：
S. Chatterjee;A. Matsumura;J. Schradermeier;G. Gillespie
多形性胶质母细胞瘤（GBM）是成人中最常见的恶性脑肿瘤，并且总是致命的。我们研究了环-（Arg-Gly-Asp-D-Phe-Val）（cRGDfV）肽在体外和体内对人恶性胶质瘤细胞存活的影响。免疫荧光分析显示，α（V）β 3整合素的存在下，U-87 MG和U-373 MG细胞，但最低的表达上U-251 MG细胞。在体外用cRGDfV（20 μ g/ml）而不是线性肽处理U-87 MG和U-373 MG细胞，导致出现圆形和松散附着的细胞，随后细胞死亡。相比之下，无论是这种环肽或其线性同系物对U-251 MG细胞的生长和形态没有任何显着的影响。通过分别用半胱天冬酶-3和半胱天冬酶-9的抑制剂DEVD-FMK和LEHD-FMK预处理（10 μ M）细胞来阻断cRGDfV处理的（20 μ g/ml）胶质瘤细胞的死亡。此外，当用cRGDfV（50 μ g/ml）处理生长为球状体的胶质瘤细胞时，球状体形成显著减少。此外，用环肽治疗scid小鼠的颅内U-87 MG肿瘤显著（p < 0.001）延长了它们的存活。这些结果表明（i）cRGDfV通过结合在其细胞表面上表达的α（v）β 3整联蛋白诱导人胶质瘤细胞凋亡，以及（ii）cRGDfV可能是一种有效且无毒的直接抗肿瘤治疗α（v）β 3表达GBM。
Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults and is invariably fatal. We have investigated the effect of cyclo-(Arg-Gly-Asp-D-Phe-Val) (cRGDfV) peptide on survival of human malignant glioma cells in vitro and in vivo. Immunofluorescent analyses revealed the presence of alpha(v)beta3 integrin on U-87MG and U-373MG cells, but minimal expression on U-251MG cells. Treatment of U-87MG and U-373MG cells in vitro with cRGDfV (20 microg/ml), but not the linear peptide, resulted in the appearance of rounded and loosely attached cells with subsequent cell death. By comparison, neither this cyclic peptide nor its linear homolog had any significant effect on growth and morphology of U-251MG cells. The death of cRGDfV-treated (20 microg/ml) glioma cells was blocked by pretreatment (10 microM) of cells with DEVD-FMK and LEHD-FMK, inhibitors of caspase-3 and caspase-9, respectively. Moreover, when glioma cells grown as spheroids were treated with cRGDfV (50 microg/ml), spheroid formation was markedly reduced. Further, treatment of intracranial U-87MG tumors in scid mice with cyclic peptide significantly (p < 0.001) prolonged their survival. These results indicated (i) that cRGDfV induced apoptosis of human glioma cells by binding alpha(v)beta3 integrin expressed on their cell surfaces and (ii) that cRGDfV may be an effective and non-toxic direct anti-tumor therapy for alpha(v)beta3-expressing GBMs.