CN115252623A - 齐墩果烷类化合物在制备N-Myc阳性肿瘤治疗药物中的应用 - Google Patents
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Abstract
本发明提供齐墩果烷类化合物在制备N‑Myc阳性肿瘤治疗药物中的应用，所述化合物为巴多索隆和甲基巴多索隆。化合物巴多索隆和甲基巴多索隆均可显著下调肿瘤细胞中N‑Myc蛋白水平，且显著下调MYCN基因和ALK、TFAP4、ODC1和E2F5等N‑Myc下游促癌靶基因的mRNA水平，最终有效抑制N‑Myc阳性肿瘤细胞的增殖能力。本发明为N‑Myc阳性肿瘤的临床治疗提供全新的治疗手段，同时也拓展了巴多索隆和甲基巴多索隆在临床疾病治疗中的应用范围，为进一步提高N‑Myc阳性肿瘤的临床治疗及改善肿瘤患者的预后提供了可能性。
Description
技术领域
本发明属于化合物的应用领域，涉及齐墩果烷类化合物在制备N-Myc阳性肿瘤治疗药物中的应用，所述化合物为Bardoxolone和Bardoxolone methyl。
背景技术
N-Myc蛋白是MYCN基因编码表达的产物，主要表达于大脑、视网膜、肾脏和人类胎儿肺部的神经上皮细胞中的未分化神经细胞，通过维持细胞的干性和增殖在胚胎发育过程中发挥至关重要的作用。N-Myc蛋白因MYCN基因扩增、蛋白稳定性增加等病理学改变在肿瘤中呈现异常高表达(N-Myc阳性)，可转录激活一系列促进细胞干性和增殖、抑制分化和凋亡的下游靶基因，进而驱动神经母细胞瘤、肾母细胞瘤、髓母细胞瘤和横纹肌肉瘤等多种肿瘤的发生发展，是公认的致癌转录因子和肿瘤不良预后指标之一。因此，针对N-Myc蛋白寻找有效的干预策略一直是肿瘤治疗领域的热点问题。
齐墩果烷类化合物Bardoxolone和Bardoxolone methyl被开发用于靶向抑制KEAP1蛋白的功能，通过增强底物蛋白NRF2的蛋白稳定性进而激活细胞的抗氧化防御系统，可发挥修复线粒体功能障碍、降低氧化应激和抑制促炎信号的作用。化合物Bardoxolonemethyl是Bardoxolone结构基础上增加一个甲基基团的衍生物，目前针对化合物Bardoxolone methyl已开展多项抗炎治疗慢性肾病的临床试验研究，包括慢性肾功能不全、局灶节段性肾小球硬化、IgA肾病和糖尿病肾病等。值得注意的是，美国食品和药物管理局授予Bardoxolone methyl孤儿药资格用于治疗Alport综合征和常染色体显性多囊性肾病(ADPKD)。另外，研究报道称Bardoxolone methyl可以抑制肿瘤发展重要信号通路NF-κB的激活，且已有相关临床试验考察Bardoxolone methyl对胰腺癌和恶性淋巴瘤患者的抗肿瘤治疗作用。但是，Bardoxolone和Bardoxolone methyl能否调控N-Myc蛋白信号且抑制N-Myc阳性肿瘤的进展是尚未见报道的。
发明内容
本发明的目的是提供一种齐墩果烷类化合物在制备N-Myc阳性肿瘤治疗药物中的应用，所述化合物为巴多索隆(Bardoxolone)，化学名为：2-氰基-3,12-二氧代齐墩果-1,9-二烯-28-酸，分子式为C31H41NO4；或甲基巴多索隆(Bardoxolone methyl)，化学名为：2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸甲酯，分子式为C32H43NO4。所述药物由齐墩果烷类化合物与药用辅料制备。
化合物Bardoxolone和Bardoxolone methyl均可显著下调N-Myc蛋白表达水平及ALK、TFAP4、ODC1和E2F5等N-Myc下游促癌靶基因的转录水平，化合物Bardoxolone methyl可有效抑制N-Myc阳性肿瘤细胞的增殖能力。
本发明提供了化合物Bardoxolone和Bardoxolone methyl作为全新干预手段用于治疗N-Myc阳性肿瘤的用途，拓展了Bardoxolone和Bardoxolone methyl在临床疾病治疗中的应用范围，相较于现有肿瘤治疗常规一线药物顺铂(Cisplatin)具有更好的治疗效果，为进一步提高N-Myc阳性肿瘤的治疗获益及改善肿瘤患者的预后提供了可能性。
附图说明
图1是确证SK-N-DZ、SK-N-BE(2)、CHP-126、SK-N-SH和SH-SY5Y等肿瘤传代细胞株的N-Myc表达水平，其中SK-N-DZ、SK-N-BE(2)和CHP-126为MYCN基因扩增型细胞株，SK-N-SH和SH-SY5Y细胞株为MYCN非基因扩增型细胞株。
图2将不同浓度的化合物Bardoxolone和Bardoxolone methyl分别作用于SK-N-DZ、SK-N-BE(2)和CHP-126等N-Myc阳性的肿瘤细胞株，N-Myc蛋白表达水平受到显著的下调。
图3是将一定浓度的化合物Bardoxolone和Bardoxolone methyl分别作用于SK-N-DZ细胞，ALK、TFAP4、ODC1和E2F5等N-Myc下游促癌靶基因的转录水平受到显著的下调。
图4是不同浓度的化合物Bardoxolone methyl对SK-N-DZ、SK-N-BE(2)和CHP-126等N-Myc阳性肿瘤细胞增殖能力的抑制作用。图中，Control对照组和Bardoxolone、Bardoxolone methyl、Cisplatin给药组之间的比较采用独立样本t检验：n.s表示p＞0.05；*表示p＜0.05；**表示p＜0.01；***表示p＜0.001。Cisplatin给药组分别和Bardoxolone、Bardoxolone methyl给药组之间的比较采用独立样本t检验：n.s表示p＞0.05；#表示p＜0.05；##表示p＜0.01；###表示p＜0.001。
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。
本发明所述的化合物Bardoxolone和Bardoxolone methyl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
收取SK-N-DZ、SK-N-BE(2)、CHP-126、SK-N-SH和SH-SY5Y细胞(购自中国科学院细胞库)，以裂解液裂解细胞抽取蛋白质，然后用N-Myc抗体(购自Cell SignalingTechnology公司)进行Western blot免疫印迹。结果显示，SK-N-DZ、SK-N-BE(2)和CHP-126细胞的N-Myc蛋白表达水平较高。结果参见图1。
实施例2
将SK-N-DZ、SK-N-BE(2)和CHP-126细胞以每孔1.5×105个的密度接种于24孔板，以不同浓度的化合物Bardoxolone(6.25×10-8～1×10-6M)、Bardoxolone methyl(3.125×10-8～5×10-7M)分别处理上述细胞，12小时后，收取细胞并裂解抽取蛋白质，然后用N-Myc抗体进行Western blot免疫印迹。结果显示，6.25×10-8～1×10-6M浓度范围的Bardoxolone可显著下调SK-N-DZ和SK-N-BE(2)两个细胞株中N-Myc的蛋白水平，结果参见图2A-B；1.25×10-7～5×10-7M浓度范围的Bardoxolone methyl可显著下调SK-N-DZ、SK-N-BE(2)和CHP-126三个细胞株中N-Myc的蛋白水平，结果参见图2C-E。
实施例3
将SK-N-DZ细胞以每孔5×105个的密度接种于6孔板，以1μM的Bardoxolone和0.5μM的Bardoxolone methyl分别处理该细胞，24小时后，用Trizol裂解液裂解细胞提取mRNA，然后用荧光定量RT-PCR进行mRNA水平检测。结果发现，Bardoxolone、Bardoxolone methyl作用可显著下调MYCN基因以及N-Myc下游促癌靶基因ALK、TFAP4、ODC1和E2F5的mRNA水平，但是对非N-Myc下游的YWHAZ基因mRNA水平无显著影响。结果参见图3A-B。
实施例4
将SK-N-DZ、SK-N-BE(2)和CHP-126细胞以每孔5000个的密度接种于96孔板，以不同浓度的化合物Bardoxolone methyl(3.125×10-8～1×10-6M)或Cisplatin(1.5625×10-7～2×10-5M)分别处理上述细胞，每个浓度作用组设置3个复孔，作用72小时之后，通过磺酰罗丹明B(SRB)染色法检测细胞的存活情况。结果显示，3.125×10-8～1×10-6M浓度范围的Bardoxolone methyl对三个N-Myc阳性肿瘤细胞株均有显著的增殖抑制作用。Bardoxolonemethyl对SK-N-DZ、SK-N-BE(2)和CHP-126细胞株的半数抑制浓度(IC50)分别为248±115nM、138±43nM和170±34nM，结果参见图4A-C，而肿瘤临床治疗一线化疗药Cisplatin在上述三个细胞株的半数抑制浓度(IC50)分别为2.69±1.04μM、7.29±0.83μM和1.32±0.06μM，结果参见图4D-F，表明在相同的肿瘤细胞上，Bardoxolone methyl相较于Cisplatin对N-Myc阳性肿瘤细胞的增殖抑制作用更加明显(248±115nM vs.2.69±1.04μM,p＜0.05，#；138±43nM vs.7.29±0.83μM,p＜0.001，###；170±34nM vs.1.32±0.06μM,p＜0.001，###)。
Claims (5)
1.一种齐墩果烷类化合物在制备N-Myc阳性肿瘤治疗药物中的应用，其特征在于，所述化合物为巴多索隆或甲基巴多索隆，巴多索隆的化学名为：2-氰基-3,12-二氧代齐墩果-1,9-二烯-28-酸，甲基巴多索隆的化学名为：2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸甲酯。
2.根据权利要求1所述的应用，其特征在于，所述的肿瘤为N-Myc阳性肿瘤，包括神经母细胞瘤、肾母细胞瘤、髓母细胞瘤或横纹肌肉瘤。
3.根据权利要求1所述的应用，其特征在于，所述的药物由药学上有效量的巴多索隆和甲基巴多索隆与药学上可接受的载体制备。
4.根据权利要求3所述的应用，其特征在于，所述载体包括常用的药用辅料辅料、生理盐水或蒸馏水。
5.根据权利要求3所述的应用，其特征在于，所述药物的剂型包括口服制剂、注射液、冻干粉针剂或大输液。
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Citations (4)
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| CN103702967A (zh) * | 2011-03-14 | 2014-04-02 | 貝丝以色列女执事医疗中心 | 用于治疗增殖性病症的方法和组合物 |
| US20160015709A1 (en) * | 2012-04-05 | 2016-01-21 | The Regents Of The University Of California | Compositions and methods for treating cancer and diseases and conditions responsive to cell growth inhibition |
| CN113197905A (zh) * | 2021-04-23 | 2021-08-03 | 浙江大学 | 三萜类化合物在制备神经母细胞瘤治疗药物中的应用 |
| US20220244263A1 (en) * | 2019-05-28 | 2022-08-04 | The Regents Of The University Of California | Methods for treating small cell neuroendocrine and related cancers |
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| CN103702967A (zh) * | 2011-03-14 | 2014-04-02 | 貝丝以色列女执事医疗中心 | 用于治疗增殖性病症的方法和组合物 |
| US20160015709A1 (en) * | 2012-04-05 | 2016-01-21 | The Regents Of The University Of California | Compositions and methods for treating cancer and diseases and conditions responsive to cell growth inhibition |
| US20220244263A1 (en) * | 2019-05-28 | 2022-08-04 | The Regents Of The University Of California | Methods for treating small cell neuroendocrine and related cancers |
| CN113197905A (zh) * | 2021-04-23 | 2021-08-03 | 浙江大学 | 三萜类化合物在制备神经母细胞瘤治疗药物中的应用 |
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| JENNIFER ALABRAN 等: "Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO", CANCER BIOLOGY & THERAPY, vol. 7, no. 5, pages 710 * |
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