CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs
CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs
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DOI：
10.1182/blood.v96.6.2246.h8002246_2246_2253
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发表时间：
2000-09-15
期刊：
影响因子：
20.3
通讯作者：
Bhalla, KN
中科院分区：
文献类型：
--
作者：
Fang, GF;Kim, CN;Bhalla, KN
研究了Bcr-Abl特异性酪氨酸激酶抑制剂CGP57148B（也称为STI-571）在人Bcr-Abl阳性的HL-60/Bcr-Abl和K562细胞中的分化和凋亡增敏作用。首先，结果表明p185 Bcr-Abl融合蛋白的异位表达诱导了急性髓性白血病（AML） HL-60细胞中的血红蛋白。暴露于低剂量阿拉伯糖胞苷（Ara-C; 10 nmol/L）可增加HL-60/Bcr-Abl细胞和表达p210 Bcr-Abl蛋白的慢性髓性白血病（CML）母细胞危像K562细胞的血红蛋白水平。与HL-60/neo相比，HL-60/Bcr-Abl和K562细胞对Ara-C、阿霉素或肿瘤坏死因子- α (tnf - α)诱导的凋亡具有抗性，这与caspase-8和Bid蛋白的加工减少以及细胞色素c （cyt c）的胞质积累减少有关。单独暴露于CGP57148B可增加HL60/Bcr-Abl和K562细胞的血红蛋白水平和CD11b表达，并诱导凋亡。CGP57148B处理下调抗凋亡XIAP、cIAP1和Bcl-x(L)，而不影响Bcl-2、Bax、Apaf-1、Fas （CD95）、Fas配体、Abl和Bcr-Abl水平。CGP57148B还能抑制bcr - abl阳性细胞的AM激酶和NF κ B的组成活性。通过异位表达I κ B的显性抑制因子来减弱NF κ B的活性，使HL-60/Bcr-Abl和K562细胞对tnf - α敏感，但对Ara-C或阿霉素诱导的凋亡不敏感。重要的是，与CGP57148B共处理可显著增加Ara-C或阿霉素诱导的HL-60/Bcr-Abl和K562细胞的凋亡。这与细胞质中cyt - c的积累和caspase-3的PARP裂解活性有关。这些体外数据表明，CGP57148B与抗白血病药物如Ara-C联合使用可能提高了体内治疗bcr - abl阳性急性白血病的疗效。（Blood. 2000;96:2246-2253） (C) 2000年由美国血液学会出版。
The differentiation and apoptosis-sensitizing effects of the Bcr-Abl-specific tyrosine kinase inhibitor CGP57148B, also known as STI-571, were determined in human Bcr-Abl-positive HL-60/Bcr-Abl and K562 cells. First, the results demonstrate that the ectopic expression of the p185 Bcr-Abl fusion protein induced hemoglobin in the acute myeloid leukemia (AML) HL-60 cells. Exposure to low-dose cytosine arabinoside (Ara-C; 10 nmol/L) increased hemoglobin levels in HL-60/Bcr-Abl and in the chronic myeloid leukemia (CML) blast crisis K562 cells, which express the p210 Bcr-Abl protein. As compared with HL-60/neo, HL-60/Bcr-Abl and K562 cells were resistant to apoptosis induced by Ara-C, doxorubicin, or tumor necrosis factor-alpha (TNF-alpha), which was associated with reduced processing of caspase-8 and Bid protein and decreased cytosolic accumulation of cytochrome c (cyt c). Exposure to CGP57148B alone increased hemoglobin levels and CD11b expression and induced apoptosis of HL60/Bcr-Abl and K562 cells. CGP57148B treatment down-regulated antiapoptotic XIAP, cIAP1, and Bcl-x(L), without affecting Bcl-2, Bax, Apaf-1, Fas (CD95), Fas ligand, Abl, and Bcr-Abl levels. CGP57148B also inhibited constitutively active AM kinase and NF kappa B in Bcr-Abl-positive cells. Attenuation of NF kappa B activity by ectopic expression of transdominant repressor of I kappa B sensitized HL-60/Bcr-Abl and K562 cells to TNF-alpha but not to apoptosis induced by Ara-C or doxorubicin. Importantly, cotreatment with CGP57148B significantly increased Ara-C- or doxorubicin-induced apoptosis of HL-60/Bcr-Abl and K562 cells. This was associated with greater cytosolic accumulation of cyt c and PARP cleavage activity of caspase-3. These in vitro data indicate that combinations of CGP57148B and antileukemic drugs such as Ara-C may have improved in vivo efficacy against Bcr-Abl-positive acute leukemia. (Blood. 2000;96:2246-2253) (C) 2000 by The American Society of Hematology.