Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Blood. 2010 Jun 24;115(25):5202-13. doi: 10.1182/blood-2009-12-259523. Epub 2010 Apr 9.
Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P = .007) and overall survival was significantly increased (P < .005) in animals treated with 30 mg/kg MLN8237 for 21 days. Induction of apoptosis and cell death by MLN8237 were confirmed in tumor cells excised from treated animals by TdT-mediated dUTP nick end labeling assay. MLN8237 is currently in phase 1 and phase 2 clinical trials in patients with advanced malignancies, and our preclinical results suggest that MLN8237 may be a promising novel targeted therapy in MM.
极光激酶 A 是一种有丝分裂激酶，可调节有丝分裂纺锤体的形成和分离。在多发性骨髓瘤（MM）中，高 Aurora-A 基因表达与中心体扩增和增殖相关；因此，抑制 MM 中的 Aurora-A 可能具有治疗益处。在这里，我们评估了小分子 Aurora-A 激酶抑制剂 MLN8237 的体外和体内抗 MM 活性。用 MLN8237 处理培养的 MM 细胞会导致有丝分裂纺锤体异常、有丝分裂积累，并通过细胞凋亡和衰老抑制细胞增殖。此外，MLN8237 上调 p53 和肿瘤抑制基因 p21 和 p27。将 MLN8237 与地塞米松、阿霉素或硼替佐米联合使用，可在体外诱导协同/相加的抗 MM 活性。使用人 MM 的异种移植鼠模型证实了 MLN8237 的体内抗 MM 活性。用 30mg/kg MLN8237 治疗 21 天的动物的肿瘤负担显著降低（P=0.007），总生存率显著提高（P<0.005）。通过 TdT 介导的 dUTP 缺口末端标记测定，在从治疗动物切除的肿瘤细胞中证实了 MLN8237 诱导的细胞凋亡和细胞死亡。MLN8237 目前正在晚期恶性肿瘤患者的 1 期和 2 期临床试验中，我们的临床前结果表明 MLN8237 可能是 MM 的一种有前途的新型靶向治疗药物。
