Combination of SK-7041, one of novel histone deacetylase inhibitors, and STI571-induced synergistic apoptosis in chronic myeloid leukemia
Combination of SK-7041, one of novel histone deacetylase inhibitors, and STI571-induced synergistic apoptosis in chronic myeloid leukemia
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DOI：
10.1097/cad.0b013e3280761a8a
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发表时间：
2007-07-01
影响因子：
2.3
通讯作者：
Yoon, Sung-Soo
中科院分区：
文献类型：
--
作者：
Kim, Byung-Su;Bae, Eunkyung;Yoon, Sung-Soo
尽管ST 1571在慢性粒细胞白血病的治疗中仍然起着关键作用，但对ST 1571的耐药性的出现是成功结局的主要障碍。因此，迫切需要增加慢性髓性白血病细胞对ST 1571的敏感性的新药物。SK-7041是一种新的杂合合成的组蛋白去乙酰化酶抑制剂，其衍生自阿司他丁A的异羟肟酸和MS-275的吡啶环。在急性和慢性髓性白血病中，检测了其作为单一药剂和与ST 1571组合的细胞毒性作用。SK-7041通过下调CDK 4、细胞周期蛋白E和细胞周期蛋白B1的表达，上调p21（CIP 1 = WAF 1）的表达，随后激活线粒体介导的半胱天冬酶途径，对白血病细胞表现出生长抑制作用。SK-7041与STI 571联合应用对慢性粒细胞白血病（K562）的生长抑制、细胞周期阻滞和诱导凋亡具有协同作用。协同效应是通过与单独SK-7041相同的机制介导的，包括减少细胞周期蛋白D1和诱导p21（CIP 1 = WAF 1）。综上所述，我们的研究结果表明SK-7041对白血病具有活性，并为克服慢性髓细胞白血病中的STI 571耐药性提供了新的前景。
Although ST1571 still plays a key role in the treatment of chronic myeloid leukemia, emergence of resistance to ST1571 is a major obstacle to successful outcome. Therefore, new agents that increase the sensitivity of chronic myeloid leukemia cells to ST1571 are urgently required. SK-7041 is a novel hybrid synthetic histone deacetylase inhibitor derived from the hydroxamic acid of trichostatin A and pyridyl ring of MS-275. Its cytotoxic effects were examined both as a single agent and in combination with ST1571 in acute and chronic myeloid leukemia. SK-7041 exhibited growth inhibition of leukemia cells by downregulation of CDK4, cyclin E and cyclin B1 expression, and by upregulation of p21(CIP1=WAF1) expression with subsequent activation of the mitochondria-mediated caspase pathway. SK-7041 showed synergism on growth inhibition, cell cycle arrest and induction of apoptosis in chronic myeloid leukemia (K562) when combined with STI571. The synergistic effect was mediated through the same mechanism as in SK-7041 alone, involving reduction of cyclin D1 and induction of p21(CIP1=WAF1). Taken together, our findings suggest that SK-7041 is active against leukemia and offers new prospects for overcoming STI571 resistance in chronic myeloid leukemia.