Lee Tina X, Packer Mark D, Huang Jie, Akhmametyeva Elena M, Kulp Samuel K, Chen Ching-Shih, Giovannini Marco, Jacob Abraham, Welling D Bradley, Chang Long-Sheng
Department of Otolaryngology, The Ohio State University College of Medicine, Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Eur J Cancer. 2009 Jun;45(9):1709-20. doi: 10.1016/j.ejca.2009.03.013. Epub 2009 Apr 7.
Vestibular schwannomas (VS) frequently express high levels of activated AKT. Small-molecule inhibitors of AKT signalling may have therapeutic potential in suppressing the growth of benign VS and malignant schwannomas.
Primary VS and Schwann cells, human malignant schwannoma HMS-97 cells and mouse Nf2(-/-) Schwann cells and schwannoma cells were prepared to investigate the growth inhibitory and anti-tumour activities of OSU-03012, a celecoxib-derived small-molecule inhibitor of phosphoinositide-dependent kinase-1. Cell proliferation assays, apoptosis, Western blot, in vivo xenograft analysis using SCID mice and immunohistochemistry were performed.
OSU-03012 inhibited cell proliferation more effectively in both VS and HMS-97 cells than in normal human Schwann cells. The IC5) of OSU-03012 at 48h was approximately 3.1 microM for VS cells and 2.6 microM for HMS-97 cells, compared with the IC(50) of greater than 12 microM for human Schwann cells. Similarly, mouse Nf2(-/-) schwannoma and Nf2(-/-) Schwann cells were more sensitive to growth inhibition by OSU-03012 than wild-type mouse Schwann cells and mouse schwannoma cells established from transgenic mice carrying the NF2 promoter-driven SV40 T-antigen gene. Like VS cells, malignant schwannoma HMS-97 cells expressed high levels of activated AKT. OSU-03012 induced apoptosis in both VS and HMS-97 cells and caused a marked reduction of AKT phosphorylation at both the Ser-308 and Thr-473 sites in a dose-dependent manner. In vivo xenograft analysis showed that OSU-03012 was well tolerated and inhibited the growth of HMS-97 schwannoma xenografts by 55% after 9 weeks of oral treatment. The anti-tumour activity correlated with reduced AKT phosphorylation.
OSU-03012 is a potential chemotherapeutic agent for VS and malignant schwannomas.
前庭神经鞘瘤（VS）经常高表达活化的AKT。AKT信号通路的小分子抑制剂在抑制良性VS和恶性神经鞘瘤生长方面可能具有治疗潜力。
制备原发性VS和雪旺细胞、人恶性神经鞘瘤HMS-97细胞以及小鼠Nf2(-/-)雪旺细胞和神经鞘瘤细胞，以研究OSU-03012（一种源自塞来昔布的磷酸肌醇依赖性激酶-1小分子抑制剂）的生长抑制和抗肿瘤活性。进行了细胞增殖测定、凋亡检测、蛋白质印迹分析、使用SCID小鼠的体内异种移植分析以及免疫组织化学检测。
与正常人雪旺细胞相比，OSU-03012在VS细胞和HMS-97细胞中更有效地抑制细胞增殖。OSU-03012在48小时时对VS细胞的IC50约为3.1微摩尔，对HMS-97细胞的IC50约为2.6微摩尔，而人雪旺细胞的IC50大于12微摩尔。同样，小鼠Nf2(-/-)神经鞘瘤和Nf2(-/-)雪旺细胞比野生型小鼠雪旺细胞以及从携带NF2启动子驱动的SV40 T抗原基因的转基因小鼠建立的小鼠神经鞘瘤细胞对OSU-03012的生长抑制更敏感。与VS细胞一样，恶性神经鞘瘤HMS-97细胞高表达活化的AKT。OSU-03012诱导VS细胞和HMS-97细胞凋亡，并以剂量依赖性方式导致Ser-308和Thr-473位点的AKT磷酸化显著降低。体内异种移植分析表明，OSU-03012耐受性良好，口服治疗9周后可抑制HMS-97神经鞘瘤异种移植瘤生长55%。抗肿瘤活性与AKT磷酸化降低相关。
OSU-03012是一种用于VS和恶性神经鞘瘤的潜在化疗药物。
