Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, USA.
Mol Carcinog. 2013 Jan;52(1):39-48. doi: 10.1002/mc.20875. Epub 2011 Oct 17.
The renal cell carcinoma (RCC) is one of the top 10 cancers in USA. The renal tumors are highly angiogenic and are resistant to conventional interventions, particularly radiotherapy. The advent of multi-specific tyrosine kinase inhibitor sorafenib has improved the progression-free survival in RCC, but overall survival in recurrent and metastatic RCC is still a concern that has lead to characterization of combinatorial regimens. Hence, we studied the effect of combination of nutlin-3, an MDM2 inhibitor, which increases p53 levels, and sorafenib in RCC. Sorafenib along with nutlin-3 synergistically inhibited the cell survival and enhanced caspase-3 cleavage leading to apoptosis in RCC. Nutlin-3 and sorafenib were more effective in reducing the migration of RCC, in combination than as single agents. Sorafenib and nutlin-3 decreased the phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) and ERK along with inducing p53 activity. The sorafenib and nutlin-3 co-treatment lead to enhanced levels of p53, p-p53, and increase in the levels of p53 pro-apoptotic effector PUMA, Bax, and decrease in the anti-apoptotic Bcl-2 levels. Importantly, our studies revealed that sorafenib alone can activate p53 in a concentration dependent manner. Thus, co-treatment of nutlin-3 with sorafenib leads to increased half-life of p53, which in turn can be activated by sorafenib, to induce downstream pro-apoptotic and anti-proliferative effects. This is the first report showing the synergistic effect of sorafenib and nutlin-3 while providing a strong clinical-translational rationale for further testing of sorafenib and nutlin-3 combinatorial regimen in human RCC.
肾细胞癌（RCC）是美国排名前 10 的癌症之一。肾肿瘤具有高度血管生成性，并且对常规干预措施（特别是放射疗法）具有抗性。多特异性酪氨酸激酶抑制剂索拉非尼的出现改善了 RCC 的无进展生存期，但复发性和转移性 RCC 的总生存期仍然令人担忧，这导致了联合方案的特征描述。因此，我们研究了 MDM2 抑制剂 nutlin-3 与索拉非尼联合应用于 RCC 的效果。索拉非尼与 nutlin-3 协同抑制细胞存活并增强 caspase-3 切割，导致 RCC 细胞凋亡。与单药治疗相比，nutlin-3 和索拉非尼联合使用更能有效地减少 RCC 的迁移。索拉非尼和 nutlin-3 降低了血管内皮生长因子受体-2（VEGFR-2）和 ERK 的磷酸化，同时诱导了 p53 活性。索拉非尼和 nutlin-3 联合治疗可提高 p53、p-p53 的水平，并增加 p53 促凋亡效应物 PUMA、Bax 的水平，降低抗凋亡 Bcl-2 的水平。重要的是，我们的研究表明，索拉非尼本身可以以浓度依赖的方式激活 p53。因此，nutlin-3 与索拉非尼联合治疗可增加 p53 的半衰期，而 p53 又可被索拉非尼激活，从而诱导下游促凋亡和抗增殖作用。这是第一项表明索拉非尼和 nutlin-3 具有协同作用的报告，同时为进一步在人类 RCC 中测试索拉非尼和 nutlin-3 联合方案提供了强有力的临床转化依据。
