Sunitinib induces PTEN expression and inhibits PDGFR signaling and migration of medulloblastoma cells.
Sunitinib induces PTEN expression and inhibits PDGFR signaling and migration of medulloblastoma cells.
复制标题
DOI：
10.1007/s11060-010-0259-9
复制
发表时间：
2011-01
影响因子：
3.9
通讯作者：
MacDonald, Tobey J.
中科院分区：
文献类型：
--
作者：
Abouantoun, Thamara J.;Castellino, Robert C.;MacDonald, Tobey J.
我们之前的研究表明，抑制血小板衍生生长因子受体(PDGFR)可以阻止髓母细胞瘤细胞的存活和迁移。寻找适合在体内进行髓母细胞瘤模型临床前试验的体外PDGFR靶向药理学药物，对于将这些药物有效地转化为儿童髓母细胞瘤的临床研究至关重要。在这项研究中，我们研究了多酪氨酸激酶抑制剂Sunitinib是否有效地抑制了髓母细胞瘤细胞迁移所需的PDGFR信号。人髓母细胞瘤DAOY和D556细胞经0.2PDGFBB处理1h后，μ-BB刺激可诱导PTEN的表达，显著抑制PDGFR信号转导活性和反式激活，且不依赖RAS。在治疗后4小时和24小时，舒尼替尼可显著减少PDGF-BB和10%血清对髓母细胞瘤细胞的迁移。用舒尼替尼处理D556细胞1h后，D556细胞脱落，细胞存活率下降，但对Daoy细胞无影响，且仅在处理后48h。然而，在任何时间点，舒尼替尼均未诱导这两种细胞的凋亡，表明舒尼替尼的抗迁移作用不是由于阻碍了细胞的存活。Smo/Smo小鼠同样可抑制原代小鼠Smo/Smo髓母细胞瘤细胞的PDGFR信号转导和迁移，提示Smo/Smo小鼠是Smo/Smo小鼠临床前试验的合适模型。这些结果表明，舒尼替尼可能是一种治疗侵袭性髓母细胞瘤的重要药理药物，特别是有证据表明它能够穿过血脑屏障到达靶向肿瘤细胞，因此需要进一步的体内试验来证实疗效。
We previously showed that inhibition of the platelet-derived growth factor receptor (PDGFR) blocks the survival and migration of medulloblastoma cells. Identification of in vitro PDGFR-targeting pharmacologic agents that are suitable for preclinical testing in medulloblastoma models in vivo will be critical for efficiently translating these agents to clinical investigation in children with medulloblastoma. In this study, we investigated whether the multi-tyrosine kinase inhibitor sunitinib, effectively inhibits PDGFR signaling required for medulloblastoma cell migration. Daoy and D556 human medulloblastoma cells pre-treated for 1 h with 0.2 μM sunitinib demonstrated induction of PTEN expression and significant inhibition of PDGFR signaling activity and transactivation of EGFR, in a RAS-independent manner, in response to PDGF-BB stimulation. Sunitinib pre-treatment markedly reduced medulloblastoma cell migration in response to both PDGF-BB and 10% serum at 4 and 24 h after treatment. Pre-treatment with sunitinib for 1 h also resulted in detachment and decreased viability of D556, but not Daoy, cells and only after 48 h following treatment. However, sunitinib did not induce apoptosis in either cell line at any time point, indicating that the anti-migratory effects of sunitinib were not due to impeding cell survival. Sunitinib similarly inhibited PDGFR signaling and migration of primary murine Smo/Smo medulloblastoma cells, suggesting that the Smo/Smo mouse is an appropriate model for preclinical testing of sunitinib. These results indicate that sunitinib may be an important pharmacologic agent for the treatment of invasive medulloblastoma, particularly given evidence of its ability to cross the blood–brain barrier to target tumor cells, and thus warrants further in vivo testing for confirmation of efficacy.
登录
查看更多内容
影响因子：
4.8
作者：
Liu, PS;Ying, YS;Anderson, RGW
通讯作者：
Anderson, RGW
影响因子：
9.8
作者：
Osusky, Katherine L.;Hallahan, Dennis E.;Geng, Luis
通讯作者：
Geng, Luis
影响因子：
4.3
作者：
McLean, Thomas W
通讯作者：
McLean, Thomas W
影响因子：
4.8
作者：
Li, J;Kim, YN;Bertics, PJ
通讯作者：
Bertics, PJ
影响因子：
158.5
作者：
Motzer, Robert J.;Hutson, Thomas E.;Figlin, Robert A.
通讯作者：
Figlin, Robert A.