Low dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruption.
Low dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruption.
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低剂量雷公藤甲素通过活性氧生成和 DNA 损伤反应破坏逆转成人急性淋巴细胞白血病细胞的化疗耐药性
DOI：
10.18632/oncotarget.13454
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发表时间：
2016-12-20
期刊：
影响因子：
--
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Zhao H;Shi P;Deng M;Jiang Z;Li Y;Kannappan V;Wang W;Li P;Xu B
化疗耐药性是急性淋巴细胞白血病（ALL）治疗的主要挑战。因此，迫切需要新的药物来克服ALL的耐药性。为此，我们建立了阿糖胞苷（araC）-耐药ALL细胞系（NALM-6/R），有趣的是，它显示出对阿霉素（ADM）的交叉耐药。在这里，我们报告，低剂量的雷公藤内酯醇（TPL），用于治疗炎症性疾病，如关节炎，可以逆转araC和ADM的耐药性和NALM-6/R细胞以及原代细胞从复发性或难治性（R/R）ALL患者，反映在体外细胞增殖抑制和诱导凋亡，并在小鼠异种移植模型的体内肿瘤生长的抑制。从机制上讲，这些事件与线粒体膜电位受损和活性氧（ROS）产生增加有关。TPL与araC或ADM联合处理可上调促凋亡caspase-9蛋白，抑制检查点激酶1（Chk 1）和2（Chk 2）磷酸化，并诱导γ H2 A. X（DNA损伤标志物）。值得注意的是，TPL和常规化疗药物的联合方案也迅速降低了R/R ALL患者的肿瘤负荷。总之，这些发现为重新利用TPL联合化疗药物治疗R/R ALL作为替代挽救方案提供了临床前证据。
Chemoresistance represents a major challenge for treatment of acute lymphoblastic leukemia (ALL). Thus, new drugs to overcome chemoresistance in ALL are urgently needed. To this end, we established a cytarabine (araC)-resistant ALL cell line (NALM-6/R), which interestingly displayed cross-resistance towards doxorubicin (ADM). Here we report that low dose of triptolide (TPL), a natural product used for treating inflammatory diseases such as arthritis, could reverse araC and ADM resistance and in NALM-6/R cells as well as primary cells from patients with relapsed or refractory (R/R) ALL, reflected by inhibition of cell proliferation and induction of apoptosis in vitro, and repression of tumor growth in vivo in a mouse xenograft model. Mechanistically, these events were associated with impaired mitochondrial membrane potential and increased reactive oxygen species (ROS) production. Co-treatment with TPL and araC or ADM upregulated pro-apoptotic caspase-9 protein, inhibited checkpoint kinase 1 (Chk1) and 2 (Chk2) phosphorylation, and induced γH2A.X (a DNA damage marker). Notably, the combination regimen of TPL and conventional chemotherapeutics also rapidly diminished tumor burden in a patient with R/R ALL. Together, these findings provide preclinical evidence for repurposing use of TPL in combination with chemotherapeutic agents to treat R/R ALL as an alternative salvage regimen.