Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB
Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB
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DOI：
10.1158/1078-0432.ccr-12-1511
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发表时间：
2013-03-15
影响因子：
11.5
通讯作者：
Shalapour, Shabnam
中科院分区：
文献类型：
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作者：
Bastian, Lorenz;Hof, Jana;Shalapour, Shabnam
目的：疾病复发和随后对现有疗法的耐药性仍然是治疗儿童B细胞前体急性淋巴细胞白血病（BCP-ALL）的主要挑战。新的治疗选择，如蛋白酶体和组蛋白脱乙酰酶抑制剂（HDACi）的毒性不同于传统的细胞毒性药物，需要为这些广泛的预处理patients.Experimental Design：抗增殖和促凋亡作用的联合HDACi/蛋白酶体抑制剂治疗进行了分析，使用BCP-ALL单培养，共培养与原发性间充质基质细胞从ALL患者，和异种移植小鼠模型。基因表达谱和蛋白validation.Results：我们确定了蛋白酶体抑制剂硼替佐米作为一个有前途的组合合作伙伴HDACi由于大量的协同抗白血病活性BCP-ALL细胞后，伴随应用的潜在的分子机制与联合治疗。在化疗药物存在下，这种作用得以维持甚至增加。HDACi/BTZ联合治疗的协同效应与参与细胞周期、JUN/MAPK、PI 3 K/AKT、p53、泛素/蛋白酶体和NF-κ B途径的基因的调节有关。我们观察到硼替佐米治疗后NF-κ B的活化和伴随治疗后诱导凋亡相关的NF-κ B靶基因如TNF α R，表明NF-κ B可能参与促凋亡介质。在这种情况下，显着降低NF-κ B B亚基基因表达检测白血病细胞的患者谁开发了一线化疗期间复发，与那些谁复发后停止一线therapy.Conclusion：这些结果提供了一个合理的整合HDACi/BTZ组合到目前的儿童BCP-ALL治疗方案。临床癌症研究; 19（6）; 1445-57。(C)2013年AACR。
Purpose: Relapse of disease and subsequent resistance to established therapies remains a major challenge in the treatment of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). New therapeutic options, such as proteasome and histone deacetylase inhibitors (HDACi) with a toxicity profile differing from that of conventional cytotoxic agents, are needed for these extensively pretreated patients.Experimental Design: Antiproliferative and proapoptotic effects of combined HDACi/proteasome inhibitor treatments were analyzed using BCP-ALL monocultures, cocultures with primary mesenchymal stroma cells from patients with ALL, and xenograft mouse models. The underlying molecular mechanisms associated with combined treatment were determined by gene expression profiling and protein validation.Results: We identified the proteasome inhibitor bortezomib as a promising combination partner for HDACi due to the substantial synergistic antileukemic activity in BCP-ALL cells after concomitant application. This effect was maintained or even increased in the presence of chemotherapeutic agents. The synergistic effect of combined HDACi/BTZ treatment was associated with the regulation of genes involved in cell cycle, JUN/MAPK, PI3K/AKT, p53, ubiquitin/proteasome, and NF-kappa B pathways. We observed an activation of NF-kappa B after bortezomib treatment and the induction of apoptosis-related NF-kappa B target genes such as TNF alpha Rs after concomitant treatment, indicating a possible involvement of NF-kappa B as proapoptotic mediator. In this context, significantly lower NF-kappa B subunits gene expression was detected in leukemia cells from patients who developed a relapse during frontline chemotherapy, compared with those who relapsed after cessation of frontline therapy.Conclusion: These results provide a rationale for the integration of HDACi/BTZ combinations into current childhood BCP-ALL treatment protocols. Clin Cancer Res; 19(6); 1445-57. (C) 2013 AACR.