Kinesin spindle protein inhibitor SB743921 induces mitotic arrest and apoptosis and overcomes imatinib resistance of chronic myeloid leukemia cells
Kinesin spindle protein inhibitor SB743921 induces mitotic arrest and apoptosis and overcomes imatinib resistance of chronic myeloid leukemia cells
复制标题
DOI：
10.3109/10428194.2014.956319
复制
发表时间：
2015-06
影响因子：
2.6
通讯作者：
Yue Yin;Huiyan Sun;Jun Xu;F. Xiao;Hua Wang;Yuefeng Yang;H. Ren;Chu-Tse Wu;Chun-ji Gao;
中科院分区：
文献类型：
--
作者：
Yue Yin;Huiyan Sun;Jun Xu;F. Xiao;Hua Wang;Yuefeng Yang;H. Ren;Chu-Tse Wu;Chun-ji Gao;
抑制细胞有丝分裂通路可能为慢性粒细胞白血病（CML）的治疗提供一种新的手段。驱动蛋白纺锤体蛋白（KSP）是一种微管相关的运动蛋白，在细胞周期进程中起重要作用，在bcr-abl+ CML细胞中过表达。逆转录病毒介导的bcr-abl转导增加脐血CD 34+细胞KSP表达SB 743921是一种选择性KSP抑制剂，正在进行的临床试验中研究用于治疗骨髓瘤，白血病和实体瘤。用SB 743921处理CML细胞导致增殖和集落形成细胞（CFC）形成能力降低。SB 743921还积极阻断细胞周期进程，导致原代CML细胞和细胞系的凋亡。KSP抑制使CML细胞对伊马替尼诱导的凋亡敏感。重要的是，SB 743921抑制各种CML细胞的增殖，包括携带T315 I突变的细胞。此外，我们证明SB 743921处理抑制CML细胞中的ERK和AKT活性。这些数据表明，SB 743921可能成为一种新的治疗药物的慢性粒细胞白血病患者。
Abstract Inhibition of the cell mitotic pathway may provide a novel means for therapeutic intervention in chronic myeloid leukemia (CML). Kinesin spindle protein (KSP), a microtubule-associated motor protein which is essential for cell cycle progression, is overexpressed in bcr–abl+ CML cells. Retrovirus mediated bcr–abl transduction increases KSP expression in cord blood CD34 + cells. SB743921 is a selective KSP inhibitor which is being investigated in ongoing clinical trials for treatment of myeloma, leukemia and solid tumors. Treatment of CML cells with SB743921 resulted in reduced proliferation and colony forming cell (CFC) formation ability. SB743921 also actively blocked cell cycle progression, leading to apoptosis in both primary CML cells and cell lines. KSP inhibition sensitized CML cells to imatinib-induced apoptosis. Importantly, SB743921 inhibited the proliferation of various CML cells including T315I mutation-harboring cells. Furthermore, we demonstrated that SB743921 treatment suppressed ERK and AKT activity in CML cells. These data indicate that SB743921 may become a novel treatment agent for patients with CML.