CN114712381B - Ak2基因在制备白血病诱导分化治疗药物中的应用 - Google Patents
Ak2基因在制备白血病诱导分化治疗药物中的应用 Download PDFInfo
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Abstract
本发明公开了AK2基因在制备白血病诱导分化治疗药物中的应用。本发明利用siRNA干扰技术，通过降低AK2的表达可以直接诱导白血病细胞发生分化。因此首次提出AK2基因是白血病诱导分化治疗的关键基因，AK2的siRNAs分子可以作为白血病诱导分化剂，为诱导分化治疗白血病提供了新的治疗靶点，在白血病的治疗中发挥重要作用。本发明为制备新的诱导分化白血病药物，提高白血病患者的疗效，改善耐药及相关预后情况提了可能性。
Description
技术领域
本发明属医药生物技术领域，具体涉及AK2(腺苷酸激酶2)基因在制备白血病诱导分化治疗药物中的应用。
背景技术
急性髓性白血病(Acute myeloid leukemia,AML)是一种骨髓与外周血中原始和幼稚髓性细胞异常增生的恶性克隆性疾病。目前其标准疗法是以蒽环类抗生素(Anthracycline)联合阿糖胞苷(Cytarabine)进行诱导治疗，随后配合化疗或干细胞移植进行巩固治疗。然而，即使在此严密的治疗下，很多病人预后极差，最终形成复发/难治性肿瘤，成年AML病人的5年生存率只有30％。分化障碍是急性髓性白血病的一个标志性特征，即造血干/祖细胞阻滞在分化成熟的早期阶段。自全反式维甲酸(All-trans retinoic acid，ATRA)首次应用于临床诱导分化治疗急性早幼粒细胞白血病(APL)获得卓越成效后，分化疗法被认为是治疗AML一项非常有前景和突破性的策略。然而，目前分化疗法仍存在临床可用药物少和适用范围窄等缺点。因此，寻找AML分化治疗的新型潜在靶标和干预手段是目前较为迫切的需求。
腺苷酸激酶2(Adenylate kinase 2,AK2)属于AK腺苷酸激酶家族，是一种调控细胞内能量转换的磷酸转移激酶，主要催化AMP和ATP反应形成两个ADP分子，维持细胞内的能量平衡，对生物体的生长发育中具有重要作用。许多研究表明AK2参与癌症的发生发展，AK2上调可以被癌细胞用来支持生物合成过程和细胞生长的能量供应。AK2在乳腺癌、肺腺癌、畸胎癌等异常高表达。研究表明AK2在肺腺癌中调控肿瘤细胞转移，AK2的敲低抑制了肺腺癌细胞的增殖、迁移和侵袭，并诱导了细胞凋亡和自噬。最近的一项研究也发现在T细胞-急性淋巴细胞白血病中存在AK2高表达，沉默AK2可通过破坏线粒体氧化磷酸化途径导致线粒体功能障碍，从而导致大量细胞凋亡。但是，目前关于AK2基因与白血病细胞分化之间的关系尚不清楚，有待进一步研究。
发明内容
本发明的目的是提供一种AK2基因在制备白血病诱导分化治疗药物中的应用，所述AK2(腺苷酸激酶2)基因核苷酸序列如SEQ ID NO:1所示，所述AK2基因编码的蛋白序列如SEQ ID NO:2所示，所述AK2基因干扰siRNAs的核苷酸序列分别为：
SEQ ID NO:3：5’GCAGCCTTTATGGGCATTACT 3’(﹟1)
SEQ ID NO:4：5’GTTGGAATAACTGGACTCTTT 3’(﹟2)
以上所述药物的制剂形式为液体制剂或固体制剂。
本发明通过应用针对AK2基因的siRNAs达到下调AK2的作用，从而研究AK2在诱导白血病细胞分化中的作用。2个针对AK2基因的siRNAs(SEQ ID NO:3；SEQ ID NO:4)均能抑制AK2的表达，进而诱导白血病细胞发生分化。具体表现为白血病HL60细胞表面分化特异性抗原CD11b及CD14的表达明显升高、细胞的NBT还原能力增强以及细胞核质比减少。
本发明采用RNA干扰技术降低AK2后发生非常明显的分化。因此，本发明不仅公开了AK2基因的应用，而且为诱导分化治疗白血病提供了新的治疗靶点。
本发明利用siRNA干扰技术，通过降低AK2的表达可以直接诱导白血病细胞发生分化。因此首次提出AK2基因是白血病诱导分化治疗的关键基因，AK2的siRNAs分子可以作为白血病诱导分化剂，在白血病的治疗中发挥重要作用。
本发明提供AK2基因在制备诱导分化治疗白血病药物中的用途，特别是AK2siRNA在制备诱导分化治疗人白血病药物中的用途。下调AK2可以有效诱导人白血病细胞的分化，为目前白血病的治疗药物的开发提供了新的方向，一定程度上解决临床上白血病诱导分化药物的可用药物少、机制单一等尴尬局面。总之，下调AK2可以诱导白血病细胞分化为白血病治疗开辟了新的研究领域，为制备新的诱导分化白血病药物，提高白血病患者的疗效，改善耐药及相关预后情况提了可能性。
附图说明
图1是2个针对AK2基因的siRNA(SEQ ID NO:3；SEQ ID NO:4)均具有显著下调AK2的蛋白表达的作用。
图2是将针对AK2基因的siRNA(SEQ ID NO:3；SEQ ID NO:4)应用于白血病细胞HL60，白血病细胞的表面分化抗原CD11b及CD14的表达水平明显提高。
图3是将针对AK2基因的siRNA(SEQ ID NO:3；SEQ ID NO:4)应用于白血病细胞HL60，白血病细胞的NBT还原能力明显增强。
图4是将针对AK2基因的siRNA(SEQ ID NO:3；SEQ ID NO:4)应用于白血病细胞HL60，白血病细胞的核形态发生明显的变化。
具体实施方式
下面结合附图和实施例对本发明作进一步详细的说明。以下实施例仅用于说明本发明而不用于限制本发明的范围。
实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆:实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。
本发明所述的AK2基因的应用，可参考常规的药物配置方法和实际开发。药物剂型和生物制剂为医学上认可的任何一种剂型，例如为粉剂、注射液、胶囊、片剂或口服液。
实施例1：
将靶向不同序列的2个AK2siRNA(SEQ ID NO:3；SEQ ID NO:4)以及阴性对照nc，通过脂质体转染法将其导入HL60细胞中(购自中国科学院细胞库)，72小时后收取细胞，细胞裂解液裂解细胞抽取蛋白质，然后用AK2抗体(购自Proteintech公司)进行Western blot免疫印迹。结果显示，以上所有的AK2 siRNA(SEQ ID NO:3；SEQ ID NO:4)均能有效的抑制AK2的蛋白表达。结果参见图1。
实施例2：
将2个靶向不同序列的AK2siRNA(如SEQ ID NO:3；SEQ ID NO:4)以及阴性对照nc，通过电转法导入白血病细胞HL60中，在处理后D3，D5及D7天收集细胞，检测细胞表面分化特异性抗原CD11b及CD14的表达。细胞用冰PBS漂洗3次后用3％BSA在室温下封闭30min，然后用CD11b-PE标记的单克隆抗体避光孵育45min，经PBS洗涤后用流式细胞仪进行检测，并用CellQuest Pro软件分析。结果发现AK2 siRNA可以明显促进白血病细胞表面特异性抗原CD11b及CD14表达。结果参见图2。
实施例3：
将2个靶向不同序列的AK2siRNA(如SEQ ID NO:3；SEQ ID NO:4)以及阴性对照nc，通过电转法导入白血病细胞HL60中，在处理后D7天收集细胞，检测细胞对NBT的还原能力。细胞采用冰PBS漂洗3次后用200ul PBS重悬，而后加入200ul NBT反应液(1ml PBS中含有2mg NBT与2ug TPA)，避光37℃反应40min。之后加入PBS 1ml终止，离心后去上清，采用甲醇固定后涂于24孔板中，显微镜下观察拍照。结果发现AK2 siRNA可以明显促进白血病细胞的NBT还原能力。结果参见图3。
实施例4：
将2个靶向不同序列的AK2siRNA(如SEQ ID NO:3；SEQ ID NO:4)以及阴性对照nc，通过电转法导入白血病细胞HL60中，在处理后D7天收集细胞，采用瑞氏-吉姆萨染色法观察细胞核形态变化。AK2 siRNA作用后，细胞核质比明显减小。结果参见图4。
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Claims (2)
1.一种靶向腺苷酸激酶2基因的干扰siRNAs在制备白血病诱导分化治疗药物中的应用，其特征在于，所述腺苷酸激酶2基因核苷酸序列如SEQ ID NO:1所示，所述腺苷酸激酶2基因编码的蛋白序列如SEQ ID NO:2所示，所述靶向腺苷酸激酶2基因的干扰siRNAs的核苷酸序列分别为：SEQ ID NO:3：5’ GAAACTGGTGAGTGATGAAAT 3’，SEQ ID NO:4：5’CGATGTCGTGTTCGCAAGCAT 3’ ，通过2个针对AK2基因的siRNAs抑制AK2的表达，进而诱导白血病细胞发生分化。
2.根据权利要求1所述的应用，其特征在于，所述药物的制剂形式为液体制剂或固体制剂。
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Citations (4)
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|---|---|---|---|---|
| CN1552735A (zh) * | 2003-12-18 | 2004-12-08 | 中国医学科学院血液学研究所 | 用于诱导白血病细胞分化及凋亡的抗cd44的工程抗体 |
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| CN101180407A (zh) * | 2005-05-18 | 2008-05-14 | 惠氏公司 | 白血病疾病基因和其用途 |
| CN103417988A (zh) * | 2013-07-20 | 2013-12-04 | 浙江大学 | Cdk2基因在制备白血病诱导分化治疗药物中的应用 |
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