Flavopiridol induces p53 via initial inhibition of Mdm2 and p21 and, independently of p53, sensitizes apoptosis-reluctant cells to tumor necrosis factor
Flavopiridol induces p53 via initial inhibition of Mdm2 and p21 and, independently of p53, sensitizes apoptosis-reluctant cells to tumor necrosis factor
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DOI：
10.1158/0008-5472.can-04-0204
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发表时间：
2004-05-15
期刊：
影响因子：
11.2
通讯作者：
Blagosklonny, MV
中科院分区：
文献类型：
--
作者：
Demidenko, ZN;Blagosklonny, MV
黄酮吡醇（FP）抑制基因表达并导致细胞凋亡，而这些作用不能通过抑制控制细胞周期的细胞周期蛋白依赖性激酶来解释。FP是一种转录抑制剂这一简单而确定的概念预测了它的作用。由于Mdm-2靶向p53降解，正如预测的那样，FP通过抑制Mdm-2显著诱导p53。一旦p53被诱导，转录恢复（通过去除FP）导致p21和Mdm-2的超诱导。同样，低浓度FP （50 nm）诱导p21和Mdm-2的初始下调。Mdm-2/p21表达的持续下降和p53的积累与浓度为> - 100 nm的FP接近最大的细胞毒性一致。p53的诱导是细胞毒性的标志，而不是原因。FP在p53-null白血病细胞中引起快速凋亡（caspase依赖性细胞死亡）。在这些细胞中，fp诱导的细胞凋亡通过半胱天冬酶抑制剂转化为生长停滞。在不愿凋亡的A549和PC3M癌细胞中，FP抑制细胞增殖，但不引起细胞凋亡。像典型的转录抑制剂一样，FP使细胞对凋亡刺激敏感，使肿瘤坏死因子在不愿凋亡的细胞中引起快速和大量的凋亡。我们讨论，作为一种可逆的转录抑制剂，FP可用于临床新的合理药物组合。
Flavopiridol (FP) inhibits gene expression and causes apoptosis, and these effects cannot be explained by inhibition of cyclin-dependent kinases that govern cell cycle. The simple and established notion that FP is an inhibitor of transcription predicts its effects. Because Mdm-2 targets p53 for degradation, FP, as predicted, dramatically induced p53 by inhibiting Mdm-2. Once p53 was induced, restoration of transcription (by removal of FP) resulted in superinduction of p21 and Mdm-2. Similarly, low concentrations of FP (50 nm) induced p21 and Mdm-2 because of their initial down-regulation. A sustained decrease of Mdm-2/p21 expression and accumulation of p53 coincided with near-maximal cytotoxicity of FP at concentrations >100 nm. Induction of p53 was a marker, not a cause, of cytotoxicity. FP caused rapid apoptosis (caspase-dependent cell death) in p53-null leukemia cells. In these cells, FP-induced apoptosis was converted to growth arrest by inhibitors of caspases. In apoptosis-reluctant A549 and PC3M cancer cells, FP inhibited cell proliferation but did not cause apoptosis. Like typical inhibitors of transcription, FP sensitized cells to apoptotic stimuli, allowing tumor necrosis factor to cause rapid and massive apoptosis in otherwise apoptosis-reluctant cells. We discuss that, as a reversible inhibitor of transcription, FP can be used clinically in novel rational drug combinations.