Sorafenib inhibits neuroblastoma cell proliferation and signaling, blocks angiogenesis, and impairs tumor growth
Sorafenib inhibits neuroblastoma cell proliferation and signaling, blocks angiogenesis, and impairs tumor growth
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DOI：
10.1002/pbc.24004
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发表时间：
2012-10-01
影响因子：
3.2
通讯作者：
Cohn, Susan L.
中科院分区：
文献类型：
--
作者：
Kakodkar, Nisha C.;Peddinti, Radhika R.;Cohn, Susan L.
目前迫切需要对高危神经母细胞瘤患儿进行更有效的治疗。临床前研究表明，神经母细胞瘤肿瘤生长可以通过阻断血管生成的药物抑制。我们假设同时靶向神经母细胞瘤细胞和肿瘤血管生成的药物将具有有效的抗肿瘤活性。在这项研究中，我们测试了索拉非尼，一种多激酶抑制剂，对神经母细胞瘤细胞增殖和信号传导的影响，以及皮下人神经母细胞瘤异种移植物或原位肾上腺肿瘤小鼠。用索拉非尼治疗皮下神经母细胞瘤异种移植物或原位肾上腺肿瘤的小鼠，并测量肿瘤生长速率。在治疗组和对照组神经母细胞瘤中，对血管结构和血管密度进行了组织学评价。还评价了索拉非尼对神经母细胞瘤增殖、细胞周期和信号传导的体外作用。结果索拉非尼对皮下和原位肾上腺肿瘤均有抑制作用。与对照组相比，治疗组肿瘤中周期性神经母细胞瘤细胞和肿瘤血管数量减少，治疗组肿瘤中的血管具有更正常的结构。索拉非尼治疗还降低了神经母细胞瘤细胞增殖，减弱ERK信号传导，并增强体外G1/G 0细胞周期阻滞。结论索拉非尼通过靶向神经母细胞瘤细胞和肿瘤血管抑制神经母细胞瘤生长。索拉非尼单药应在未来的II期神经母细胞瘤研究中进行评估。儿科血液癌症2012;59：642647。(c)2011 Wiley Periodicals，Inc.
Background More effective therapy for children with high-risk neuroblastoma is desperately needed. Preclinical studies have shown that neuroblastoma tumor growth can be inhibited by agents that block angiogenesis. We hypothesized that drugs which target both neuroblastoma cells and tumor angiogenesis would have potent anti-tumor activity. In this study we tested the effects of sorafenib, a multi-kinase inhibitor, on neuroblastoma cell proliferation and signaling, and in mice with subcutaneous human neuroblastoma xenografts or orthotopic adrenal tumors. Procedure Mice with subcutaneous neuroblastoma xenografts or orthotopic adrenal tumors were treated with sorafenib, and tumor growth rates were measured. Blood vessel architecture and vascular density were evaluated histologically in treated and control neuroblastoma tumors. The in vitro effects of sorafenib on neuroblastoma proliferation, cell cycle, and signaling were also evaluated. Results Sorafenib inhibited tumor growth in mice with subcutaneous and orthotopic adrenal tumors. Decreased numbers of cycling neuroblastoma cells and tumor blood vessels were seen in treated versus control tumors, and the blood vessels in the treated tumors had more normal architecture. Sorafenib treatment also decreased neuroblastoma cell proliferation, attenuated ERK signaling, and enhanced G1/G0 cell cycle arrest in vitro. Conclusions Our results demonstrate that sorafenib inhibits the growth of neuroblastoma tumors by targeting both neuroblastoma cells and tumor blood vessels. Single agent sorafenib should be evaluated in future phase II neuroblastoma studies. Pediatr Blood Cancer 2012;59:642647. (c) 2011 Wiley Periodicals, Inc.