CN109223774A - NF-κB信号通路抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用 - Google Patents

NF-κB信号通路抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用 Download PDF

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CN109223774A
CN109223774A CN201811110502.4A CN201811110502A CN109223774A CN 109223774 A CN109223774 A CN 109223774A CN 201811110502 A CN201811110502 A CN 201811110502A CN 109223774 A CN109223774 A CN 109223774A
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lymphatic leukemia
acute lymphatic
recurrence
signal pathway
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段才闻
陈亚莉
张梦怡
唐超
周斌兵
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Shanghai Childrens Medical Center Affiliated to Shanghai Jiaotong University School of Medicine
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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Abstract

NF‑κB信号通路抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用，它涉及一种分子调控剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用。本发明以NF‑κB信号通路抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分。本发明根据急性淋巴细胞性白血病治疗后耐药复发的分子机制，建立了全新体系的治疗药物，可实现靶向给药，对降低儿童急性淋巴细胞性白血病化疗后患儿的复发率具有重大意义。

Description

NF-κB信号通路抑制剂在制备抑制急性淋巴细胞性白血病复 发的药物中的应用
技术领域
本发明涉及一种分子调控剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用。
背景技术
白血病是造血系统的恶性增生性疾病，急性白血病占儿童白血病的90％以上，其中又以急性淋巴细胞白血病(ALL)为多见，约占65％。化疗是目前治疗ALL的主要治疗措施，欧美发达国家ALL采用化疗手段治疗5年生存率已经达到78％～85％。但仍有15％～20％的患儿会复发，复发后的治愈率不足40％。
发明内容
本发明针对儿童ALL化疗后患儿复发率高、复发患儿治愈率低的问题，提供了一种NF-KB信号通路抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用。
本发明以NF-κB信号通路抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分。
ALL细胞移植后浸润并破坏正常的骨髓微环境结构，目前临床上治疗ALL的化疗药物多为抗代谢类药物，包括阿糖胞苷(Ara-C)和嘌呤(如6-MP和6-TG)，其作用机制主要是抑制DNA合成中所需的叶酸、嘌呤、嘧啶及嘧啶核苷的合成途径，从而抑制肿瘤细胞的生存和复制所必需的代谢途径，进而导致肿瘤细胞的死亡。这些抗代谢类化疗药抑制DNA的合成，诱使细胞发生DNA损伤反应(DDR)并分泌细胞因子。化疗后ALL细胞分泌的细胞因子(CCL3、CCL4和GDF15)招募正常的骨髓细胞来重建动态演化微环境(NSM-niche)，借此保护残留的ALL细胞，从而导致儿童ALL化疗后仍有15％～20％的患儿复发，并产生耐药性。
本发明经过实验验证化疗处理导致NF-κB信号通路被激活，NF-κB信号通路的抑制可逆转残留ALL细胞分泌细胞因子的上调。通过阻断NF-κB信号通路联合化疗，有效地提高急淋细胞对化疗的敏感性，大幅减少残留ALL细胞的数量。本发明采用不同于现有抗代谢类药物的NF-κB信号通路抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分，根据急性淋巴细胞性白血病治疗后耐药复发的分子机制，建立了全新体系的治疗药物，可实现靶向给药，对降低儿童急性淋巴细胞性白血病化疗后患儿的复发率具有重大意义。
具体实施方式
本发明技术方案不局限于以下所列举具体实施方式，还包括各具体实施方式间的任意组合。
具体实施方式一：本实施方式以NF-κB信号通路抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分；特别是制备抑制儿童急性淋巴细胞性白血病化疗后复发药物中的活性成分。
具体实施方式二：本实施方式以NF-κB信号通路抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分；所述NF-κB信号通路抑制剂为抑制剂PDTC、DHMEQracemate、(-)-DHMEQ、抑制剂SC-514或抑制剂CHS-828。
本实施方式中NF-κB信号通路抑制剂PDTC、DHMEQ racemate、(-)-DHMEQ、抑制剂SC-514和抑制剂CHS-828均购自MCE公司。
实施例1
1、急淋细胞化疗后上调表达细胞因子
采用化疗药物Ara-C处理两种急性淋巴细胞性白血病细胞系(Nalm-6和Reh)，利用RT-PCR等技术检测细胞因子(CCL3，CCL4和GDF-15)的表达水平，发现细胞中CCL3，CCL4和GDF-15的mRNA水平明显上升。
2、化疗后对转录因子NF-κB产生的IκB蛋白水平及其组成部分p65进行检测
本实施例采用不同浓度的Ara-C处理ALL细胞系(Nalm-6和Reh)，提取细胞总蛋白IκB蛋白水平下降且具有剂量依赖性，而在Nalm6和Reh细胞系中p65转移到细胞核内，显示阿糖胞苷处理会激活NF-κB信号通路。本实施例还利用免疫荧光(IF)检测到在原代ALL细胞中DDR途径相关蛋白的表达也明显上升。数据表明化疗药物处理细胞可以诱导DDR信号通路激活。
采用ShRNA慢病毒包装技术，分别构建Nalm-6和Reh两种白血病细胞系NF-κBknockdown(NF-κB-KD敲除NF-κB基因的急性淋巴细胞性白血病细胞株)及对照共4种稳定的细胞株，然后用Ara-C处理，用RT-PCR技术来检测CCL3、CCL4和GDF-15的mRNA表达水平，发现在NF-κB-KD细胞中Ara-C处理后细胞因子的表达水平明显降低。
3、体内实验
实验组A：建立了Nalm6-P65-KD-GFP(敲除NF-κB基因片段P65并携带的绿色荧光蛋白急性淋巴细胞性白血病细胞株)异种移植小鼠模型，且移植细胞已经渗透到颅骨的全部血管中，用化疗药物Ara-C(50mg/kg)处理2天；实验组B：建立Nalm6-Ctr-GFP异种移植小鼠模型，且移植细胞已经渗透到颅骨的全部血管中，用含抑制剂PDTC(80mg/kg)的化疗药物Ara-C(50mg/kg)处理2天；实验组C：建立Nalm6-Ctr-GFP异种移植小鼠模型，且移植细胞已经渗透到颅骨的全部血管中，用化疗药物Ara-C处理2天。
治疗后检测发现，A组小鼠和B组小鼠中残留的GFP+ALL细胞比C组小鼠显著的降低；同时检测化疗后小鼠骨髓中残留的GFP+ALL细胞，发现在C组小鼠的骨髓中有超过10％的GFP+ALL细胞，而A组和B组小鼠的骨髓中GFP+ALL细胞不超过5％。实验结果表明，阻断了NF-κB信号通路小鼠体内ALL细胞提高了对化疗药物Ara-C的敏感性。
GFP：绿色荧光蛋白。

Claims (3)

1.NF-κB信号通路抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用，其特征在于以NF-κB信号通路抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分。
2.根据权利要求1所述的应用，其特征在于所述急性淋巴细胞性白血病为儿童急性淋巴细胞性白血病。
3.根据权利要求1所述的应用，其特征在于所述NF-κB信号通路抑制剂为抑制剂PDTC、DHMEQ racemate、(-)-DHMEQ、抑制剂SC-514或抑制剂CHS-828。
CN201811110502.4A 2018-09-21 2018-09-21 NF-κB信号通路抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用 Pending CN109223774A (zh)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110268722A1 (en) * 2010-04-22 2011-11-03 Siegelin Markus D Combination therapies with mitochondrial-targeted anti-tumor agents

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US20110268722A1 (en) * 2010-04-22 2011-11-03 Siegelin Markus D Combination therapies with mitochondrial-targeted anti-tumor agents

Non-Patent Citations (4)

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Title
MUXIANG ZHOU等: "Transfection of a dominant-negative mutant NF-kB inhibitor (IkBm) represses p53-dependent apoptosis in acute lymphoblastic leukemia cells: Interaction of IkBm and p53", 《ONCOGENE》 *
SHWU Y. TSAI等，: "Treatment of Jurkat acute T-lymphocytic leukemia cells by onconase (Ranpirnase) is accompanied by an altered nucleocytoplasmic distribution and reduced expression of transcription factor NF-κB", 《INTERNATIONAL JOURNAL OF ONCOLOGY》 *
付利等: "NF-κB抑制剂PDTC对人白血病Jurkat细胞凋亡及MMP-9表达的影响", 《中国生化药物杂志》 *
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Application publication date: 20190118