Synergistic growth inhibition based on small-molecule p53 activation as treatment for intraocular melanoma
Synergistic growth inhibition based on small-molecule p53 activation as treatment for intraocular melanoma
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DOI：
10.1038/onc.2011.309
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发表时间：
2012-03-01
期刊：
影响因子：
8
通讯作者：
Jochemsen, A. G.
中科院分区：
文献类型：
--
作者：
de Lange, J.;Ly, L. V.;Jochemsen, A. G.
葡萄膜黑色素瘤患者的预后很差。由于目前的治疗效果有限，需要开发新的治疗策略。因为p53突变在葡萄膜黑色素瘤中不常见，所以p53的再激活可用于实现肿瘤消退。我们研究了基于p53激活剂Nutlin-3和p53再激活和诱导肿瘤细胞凋亡（RITA）以及拓扑异构酶I抑制剂Topotecan的联合治疗眼内黑色素瘤的用途。Nutlin-3处理诱导p53依赖的人葡萄膜黑色素瘤细胞系的生长抑制。所研究的细胞系对Nutlin-3的敏感性与基础Hdm 2或Hdmx水平无关。Nutlin-3与RITA和拓扑替康协同诱导葡萄膜黑色素瘤细胞系和短期培养物的凋亡。药物协同作用与p53-Ser 46磷酸化的增强诱导相关，而ATM抑制则减弱了这种诱导。Nutlin-3和托泊替康还显著延迟了眼部黑色素瘤的鼠B16 F10模型中的体内肿瘤生长。联合治疗似乎比单独使用任何一种药物更有效地抑制肿瘤生长。Nutlin-3、RITA和拓扑替康在常氧和缺氧下导致相当的p53活化和生长抑制。用Nutlin-3或RITA治疗对缺氧诱导的HIF-1 α没有影响，而这两种药物的组合确实抑制了缺氧诱导的HIF-1 α。此外，托泊替康单独或与Nutlin-3组合，降低HIF-1 α蛋白水平，表明p53介导的HIF-1 α下调需要一定水平的DNA损伤反应。总之，基于小分子诱导的p53激活的联合治疗可能对葡萄膜黑色素瘤具有临床潜力。Oncogene（2012）31，1105-1116; doi：10.1038/onc.2011.309; 2011年7月18日在线发表
The prognosis of patients with uveal melanoma is poor. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. Because p53 mutations are uncommon in uveal melanoma, reactivation of p53 may be used to achieve tumor regression. We investigated the use of combination therapies for intraocular melanoma, based on the p53 activators Nutlin-3 and reactivation of p53 and induction of tumor cell apoptosis (RITA) and the topoisomerase I inhibitor Topotecan. Nutlin-3 treatment induced p53-dependent growth inhibition in human uveal melanoma cell lines. The sensitivity to Nutlin-3 of the investigated cell lines did not correlate with basal Hdm2 or Hdmx levels. Nutlin-3 synergized with RITA and Topotecan to induce apoptosis in uveal melanoma cell lines and short-term cultures. Drug synergy correlated with enhanced induction of p53-Ser46 phosphorylation, which was attenuated by ATM inhibition. Nutlin-3 and Topotecan also significantly delayed tumor growth in vivo in a murine B16F10 model for ocular melanoma. Combination treatment appeared to inhibit tumor growth slightly more efficient than either drug alone. Nutlin-3, RITA and Topotecan lead to comparable p53 activation and growth inhibition under normoxia and hypoxia. Treatment with Nutlin-3 or RITA had no effect on HIF-1 alpha induction by hypoxia, whereas the combination of these two drugs did inhibit hypoxia-induced HIF-1 alpha. Also Topotecan, alone or in combination with Nutlin-3, reduced HIF-1 alpha protein levels, suggesting that a certain level of DNA damage response is required for p53-mediated downregulation of HIF-1 alpha. In conclusion, combination treatments based on small-molecule-induced p53 activation may have clinical potential for uveal melanoma. Oncogene (2012) 31, 1105-1116; doi:10.1038/onc.2011.309; published online 18 July 2011