Yang Fan, Van Meter Timothy E, Buettner Ralf, Hedvat Michael, Liang Wei, Kowolik Claudia M, Mepani Nilesh, Mirosevich Janni, Nam Sangkil, Chen Mike Y, Tye Gary, Kirschbaum Mark, Jove Richard
Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
Mol Cancer Ther. 2008 Nov;7(11):3519-26. doi: 10.1158/1535-7163.MCT-08-0138.
Medulloblastomas are the most frequent malignant brain tumors in children. Sorafenib (Nexavar, BAY43-9006), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in a variety of tumor cells. Sorafenib inhibited proliferation and induced apoptosis in two established cell lines (Daoy and D283) and a primary culture (VC312) of human medulloblastomas. In addition, sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) in both cell lines and primary tumor cells. The inhibition of phosphorylated STAT3 (Tyr(705)) occurs in a dose- and time-dependent manner. In contrast, AKT (protein kinase B) was only decreased in D283 and VC312 medulloblastoma cells and mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2) were not inhibited by sorafenib in these cells. Both D-type cyclins (D1, D2, and D3) and E-type cyclin were down-regulated by sorafenib. Also, expression of the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was decreased and correlated with apoptosis induced by sorafenib. Finally, sorafenib suppressed the growth of human medulloblastoma cells in a mouse xenograft model. Together, our data show that sorafenib blocks STAT3 signaling as well as expression of cell cycle and apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in medulloblastomas. These findings provide a rationale for treatment of pediatric medulloblastomas with sorafenib.
髓母细胞瘤是儿童中最常见的恶性脑肿瘤。索拉非尼（多吉美，BAY43 - 9006），一种多激酶抑制剂，可阻断多种肿瘤细胞的增殖并诱导其凋亡。索拉非尼抑制了两种已建立的人髓母细胞瘤细胞系（Daoy和D283）以及原代培养物（VC312）的增殖并诱导了凋亡。此外，索拉非尼在这两种细胞系和原发性肿瘤细胞中均抑制了信号转导和转录激活因子3（STAT3）的磷酸化。磷酸化STAT3（Tyr(705)）的抑制呈剂量和时间依赖性。相比之下，AKT（蛋白激酶B）仅在D283和VC312髓母细胞瘤细胞中减少，而丝裂原活化蛋白激酶（细胞外信号调节激酶1/2）在这些细胞中未被索拉非尼抑制。D型细胞周期蛋白（D1、D2和D3）以及E型细胞周期蛋白均被索拉非尼下调。此外，抗凋亡蛋白Mcl - 1（Bcl - 2家族成员）的表达降低，且与索拉非尼诱导的凋亡相关。最后，索拉非尼在小鼠异种移植模型中抑制了人髓母细胞瘤细胞的生长。总之，我们的数据表明索拉非尼阻断了STAT3信号通路以及细胞周期和凋亡调节蛋白的表达，这与髓母细胞瘤中细胞增殖的抑制和凋亡的诱导相关。这些发现为用索拉非尼治疗儿童髓母细胞瘤提供了理论依据。
