Synergistic decrease of clonal proliferation, induction of differentiation, and apoptosis of acute promyelocytic leukemia cells after combined treatment with novel 20-epi vitamin D3 analogs and 9-cis retinoic acid.
Synergistic decrease of clonal proliferation, induction of differentiation, and apoptosis of acute promyelocytic leukemia cells after combined treatment with novel 20-epi vitamin D3 analogs and 9-cis retinoic acid.
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新型20-epi维生素D3类似物和9-顺式视黄酸联合治疗后，协同减少急性早幼粒细胞白血病细胞的克隆增殖、诱导分化和凋亡。
DOI：
10.1172/jci119164
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Koeffler,HP
中科院分区：
文献类型：
--
作者：
Elstner,E;Linker-Israeli,M;Le,J;Umiel,T;Michl,P;Said,JW;Binderup,L;Reed,JC;Koeffler,HP
急性早幼粒细胞白血病（APL）患者通常在全反式维甲酸（RA）治疗后复发，因为这种治疗不能根除恶性克隆。我们的数据显示，KH 1060和其他20-epi维生素D3类似物单独是APL细胞系NB4细胞克隆生长的有效抑制剂（ED50，约5 × 10(-11) M）。KH 1060和9-顺式ra的联合作用协同且不可逆地增强了这一作用。KH 1060和9-顺式ra （10(-6) M, 3 d）均不是NB4细胞分化的强诱导剂。然而，在暴露于这两种化合物的组合后，98%的细胞分化为具有粒细胞和单核细胞特征的成熟表型。NB4细胞仅在9-顺式ra单独（28%）或9-顺式ra加KH1060联合（32%）孵育后凋亡增加。免疫组织化学显示，与KH 1060和9-顺式ra联合培养后，bcl-2蛋白在野生型NB4细胞中的表达率从接近100%下降到2%，bax蛋白在两种类似物联合培养后（5 × 10(-7) M, 3 d）从50%上升到92%。Western blot分析与这些结果相一致。对一名未治疗个体的APL细胞的研究与我们的NB4细胞的结果相似。综上所述，这些数据表明，当暴露于KH 1060和9-顺式ra的组合时，几乎所有的NB4细胞都可以被不可逆地诱导最终分化。
Patients with acute promyelocytic leukemia (APL) usually relapse after all-trans retinoic acid (RA) treatment because this therapy fails to eradicate the malignant clone. Our data showed that KH 1060 and other 20-epi vitamin D3 analogs alone were potent inhibitors of clonal growth of NB4 cells, an APL cell line (ED50, approximately 5 x 10(-11) M). The combination of KH 1060 and 9-cis-RA synergistically and irreversibly enhanced this effect. Neither KH 1060 nor 9-cis-RA (10(-6) M, 3 d) were strong inducers of differentiation of NB4 cells. However, 98% of the cells underwent differentiation to a mature phenotype with features of both granulocytes and monocytes after exposure to a combination of both compounds. Apoptosis only increased after incubation of NB4 cells with 9-cis-RA alone (28%) or with a combination of 9-cis-RA plus KH1060 (32%). Immunohistochemistry showed that the bcl-2 protein decreased from nearly 100% of the wild-type NB4 cells to 2% after incubation with a combination of KH 1060 and 9-cis-RA, and the bax protein increased from 50% of wild-type NB4 cells to 92% after culture with both analogs (5 x 10(-7) M, 3 d). Western blot analysis paralleled these results. Studies of APL cells from one untreated individual paralleled our results with NB4 cells. Taken together, the data demonstrated that nearly all of the NB4 cells can be irreversibly induced to differentiate terminally when exposed to the combination of KH 1060 and 9-cis-RA.
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影响因子：
11.2
作者：
Zi X. Chen;Theodore Il Breitman
通讯作者：
Zi X. Chen;Theodore Il Breitman
bcl-2癌基因和细胞凋亡。
影响因子：
7.8
作者：
D. Hockenbery
通讯作者：
D. Hockenbery
视黄酸和维生素 D 信号通路之间的相互作用。
影响因子：
4.8
作者：
M. Schräder;I. Bendik;M. Becker‐André;C. Carlberg
通讯作者：
C. Carlberg
影响因子：
56.9
作者：
WRIGHT, SD;RAMOS, RA;MATHISON, JC
通讯作者：
MATHISON, JC
视黄酸和粒细胞集落刺激因子协同诱导急性早幼粒细胞白血病细胞中的白细胞碱性磷酸酶。
影响因子：
20.3
作者：
Maurizio Giannl;M. Terao;S. Zanotta;T. Barbui;A. Rambaldi;E. Garattini
通讯作者：
E. Garattini