Enhancement of TPA-induced growth inhibition and apoptosis in myeloid leukemia cells by BAY 11-7082, an NF-kappaB inhibitor.
Enhancement of TPA-induced growth inhibition and apoptosis in myeloid leukemia cells by BAY 11-7082, an NF-kappaB inhibitor.
复制标题
DOI：
10.3892/ijo.27.4.941
复制
发表时间：
2005-10
影响因子：
5.2
通讯作者：
A. Hansson;Yarí E. Marín;J. Suh;A. Rabson;Suzie Chen;E. Huberman;R. Chang;A. Conney;Xi Zheng
中科院分区：
文献类型：
--
作者：
A. Hansson;Yarí E. Marín;J. Suh;A. Rabson;Suzie Chen;E. Huberman;R. Chang;A. Conney;Xi Zheng
佛波醇酯，12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）是髓系白血病细胞分化和凋亡的有效刺激剂。在本研究中，我们研究了转录因子NF-κ B在TPA诱导的髓系白血病HL-60细胞系及其TPA耐药细胞HL-525的生长抑制和凋亡中的作用。与亲本细胞系不同，HL-525细胞是蛋白激酶C（PKC）-β缺陷的，并且对TPA诱导的分化和凋亡具有抗性。我们发现，TPA处理HL-60细胞导致浓度依赖性的生长抑制和凋亡细胞的增加。TPA对HL-525细胞生长和凋亡的影响较小。用TPA（0.64-3.2 nM）处理HL-60细胞引起NF-κ B的快速活化，如通过电泳迁移率变动分析（EMSA）和免疫细胞化学所确定的。尽管HL-60细胞的NF-κ B活性基础水平较低，但TPA耐药HL-525细胞的NF-κ B活性基础水平较高。用更高浓度的TPA（16-80 nM）处理HL-525细胞导致NF-kappaB活性进一步增加。发现抑制IkappaB α磷酸化并因此降低NF-κ B活化的（E）3-[（4-甲基苯基）-磺酰基]-2-丙烯腈（BAY 11-7082; BAY）降低TPA诱导的NF-κ B的核转位。BAY可增强TPA对HL-60和HL-525细胞的生长抑制和凋亡作用。本研究的结果表明，BAY对NF-κ B的抑制与TPA诱导的人髓性白血病细胞生长抑制和凋亡增强有关。TPA与NF-κ B抑制剂联合应用可提高TPA的疗效，克服部分髓系白血病患者对TPA的耐药性。
The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent stimulator of differentiation and apoptosis in myeloid leukemia cells. In the present study, we investigated the role of the transcription factor NF-kappaB in TPA-induced growth inhibition and apoptosis in the myeloid leukemia HL-60 cell line and its TPA-resistant cell variant HL-525. Unlike the parental cell line, HL-525 cells are protein kinase C (PKC)-beta deficient and resistant to TPA-induced differentiation and apoptosis. We found that treatment of HL-60 cells with TPA resulted in a concentration-dependent growth inhibition and an increase in apoptotic cells. TPA only had a small effect on growth and apoptosis in HL-525 cells. Treatment of HL-60 cells with TPA (0.64-3.2 nM) caused a rapid activation of NF-kappaB as determined by electrophoresis mobility shift assay (EMSA) and immunocytochemistry. Although the basal level of NF-kappaB activity was low in HL-60 cells, TPA-resistant HL-525 cells had a high basal level of NF-kappaB activity. Treatment of HL-525 cells with higher concentrations of TPA (16-80 nM) resulted in a further increase in NF-kappaB activity. (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY 11-7082; BAY), which inhibits IkappaB alpha phosphorylation and thus decreases NF-kappaB activation, was found to decrease TPA-induced nuclear translocation of NF-kappaB. Furthermore, BAY enhanced TPA-induced growth inhibition and apoptosis in both HL-60 and HL-525 cells. Results from the present study indicate that inhibition of NF-kappaB by BAY was associated with enhanced TPA-induced growth inhibition and apoptosis in human myeloid leukemia cells. TPA in combination with pharmacological inhibitors of NF-kappaB may improve the therapeutic efficacy of TPA and overcome the resistance to TPA in some myeloid leukemia patients.