Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol
Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol
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DOI：
10.1182/blood.v91.2.458.458_458_465
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发表时间：
1998-01-15
期刊：
影响因子：
20.3
通讯作者：
Senderowicz, AM
中科院分区：
文献类型：
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作者：
Parker, BW;Kaur, G;Senderowicz, AM
Flavopiridol（NSC 649890; Behringwerke L 86 -8275，马尔堡，德国）是细胞周期蛋白依赖性激酶（CDK）1、2和4的有效抑制剂。它在体外具有有效的抗增殖作用，并在体内肿瘤模型中具有活性。在调查flavopiridol对不同细胞类型中细胞周期进程的影响时，我们发现造血细胞系，包括SUDHL 4、SUDHL 6（B细胞系）、Jurkat和MOLT 4（T细胞系）以及HL 60（骨髓），对flavopiridol诱导的细胞凋亡显示出显著的敏感性。例如，在100 nmol/L处理12小时后，SUDHL 4细胞显示出与仅在3，000 nmol/L处理48小时后抗凋亡PC 3前列腺癌细胞所显示的相似程度的DNA片段化。暴露于1，000 nmol/L flavopiridol 12小时后，在SUDHL 4细胞中观察到典型的凋亡形态，但在PC 3前列腺癌细胞中未观察到，尽管在引起50%生长抑制（IC 50）方面具有相当的效力（SUDHL 4：120 nmol/L; PC 3：203 nmol/L）。Flavopiridol不诱导拓扑异构酶I或II可裂解的复合物活性。p53、bcl 2或bar蛋白水平与SUDHL 4细胞凋亡之间的关系未被发现。虽然flavopiridol引起细胞周期阻滞与CDK 1活性下降的PC 3细胞，SUDHL 4细胞发生凋亡的细胞周期阻滞的证据。这些结果表明，flavopiridol的抗增殖活性（表现为细胞周期阻滞）可以在不同的细胞类型中与诱导细胞凋亡的能力分开。在这有限的样本中，来自造血肿瘤的细胞似乎对flavopiridol诱导的细胞凋亡非常敏感，因此造血肿瘤的临床试验应优先考虑。(C)1998年，美国血液学会。
Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cycle progression in different cell types, we discovered that hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite comparable potency (SUDHL4:120 nmol/L; PC3: 203 nmol/L) in causing growth inhibition by 50% (IC50). Flavopiridol did not induce topoisomerase I or II cleavable complex activity. A relation of p53, bcl2, or bar protein levels to apoptosis in SUDHL4 was not appreciated. While flavopiridol caused cell cycle arrest with decline in CDK1 activity in PC3 cells, apoptosis of SUDHL4 cells occurred without evidence of cell cycle arrest. These results suggest that antiproliferative activity of flavopiridol (manifest by cell cycle arrest) may be separated in different cell types from a capacity to induce apoptosis. Cells from hematopoietic neoplasms appear in this limited sample to be very susceptible to flavopiridol-induced apoptosis and therefore clinical trials in hematopoietic neoplasms should be of high priority. (C) 1998 by The American Society of Hematology.