Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells.
Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells.
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动蛋白纺锤体蛋白(KSP)是一种微管相关的运动蛋白，对细胞周期进程至关重要，在许多癌症中过表达，是潜在的抗肿瘤靶点。我们发现，选择性抑制剂ARRY-520抑制KSP可阻断细胞周期进程，导致高表达KSP的急性髓系白血病细胞株发生凋亡。P53基因敲除、XIAP过表达和caspase-8基因突变对ARRY-520的敏感性没有显著影响，提示这种反应不依赖于P53、XIAP和外源性的凋亡途径。虽然ARRY-520诱导了HL-60和Bcl2过表达的HL-60Bcl2细胞的有丝分裂停滞，但在HL-60Bcl2细胞中细胞死亡被钝化，这表明凋亡程序是通过线粒体途径执行的。因此，ABT-737与ARRY-520对HL-60Bcl-2细胞中Bcl2的抑制作用具有协同作用。此外，在HL-60细胞中，ARRY-520在caspase激活之前增加了Bim蛋白水平。Arry-520显著抑制SCID小鼠移植瘤生长，抑制AML原始细胞生长，但不能抑制正常集落形成，支持KSP在白血病祖细胞增殖中的关键作用。这些结果表明，ARRY-520通过线粒体途径有效地诱导白血病细胞的细胞周期停滞和随后的死亡，并具有消除AML祖细胞的潜力。
Kinesin spindle protein (KSP), a microtubule-associated motor protein essential for cell cycle progression, is overexpressed in many cancers and a potential anti-tumor target. We found that inhibition of KSP by a selective inhibitor, ARRY-520, blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines which express high levels of KSP. Knockdown of p53, overexpression of XIAP, and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP, and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Accordingly, inhibition of Bcl-2 by ABT-737 was synergistic with ARRY-520 in HL-60Bcl-2 cells. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells. ARRY-520 significantly inhibited tumor growth of xenografts in SCID mice and inhibited AML blast but not normal colony formation, supporting a critical role for KSP in proliferation of leukemic progenitor cells. These results demonstrate that ARRY-520 potently induces cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway and has potential to eradicate AML progenitor cells.
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