CN116270624A - Tubastatin A的新应用 - Google Patents
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Abstract
本发明公开了Tubastatin A的新应用。发明人利用生物素质谱实验证实Tubastatin A能与GPX4直接结合；利用细胞内外GPX4酶活性实验证实Tubastatin A能以浓度及时间依赖的方式抑制GPX4酶活性，证实Tubastatin A是强效的GPX4抑制剂。Tubastatin A这一新应用与已知应用不接近，且不容易想到。更重要的是，与其他GPX4抑制剂相比，Tubastatin A体内利用度强，能显著诱导肿瘤细胞铁死亡的发生。Tubastatin A和现有的铁死亡诱导剂Erastin及RSL3联用可强力的诱导肿瘤细胞死亡。
Description
技术领域
本发明涉及化合物的新应用，具体涉及Tubastatin A的新应用。
背景技术
GPX4（谷胱甘肽过氧化物酶4）是肿瘤细胞抵抗铁死亡的关键蛋白。抑制GPX4能诱导肿瘤细胞铁死亡的发生。以GPX4为靶标，可以评价化合物的抗肿瘤活性，筛选潜在的抗肿瘤药物。然而现有的GPX4抑制剂体内利用度差，诱导铁死亡的能力不强。阳性对照药物的缺失，导致现有基于GPX4的药物筛选效率较为低下。通过抑制GPX4表达还可能发挥抑制肿瘤增殖的作用。
铁死亡（Ferroptosis ）是一种铁依赖性的，区别于细胞凋亡、细胞坏死、细胞自噬的新型的细胞程序性死亡方式。铁死亡的主要机制是，在二价铁或酯氧合酶的作用下，催化细胞膜上高表达的不饱和脂肪酸，发生脂质过氧化，从而诱导细胞死亡。最近的研究表明，铁死亡与许多疾病的病理生理过程密切相关，如肿瘤、神经系统疾病、缺血再灌注损伤、肾损伤和血液疾病。如何通过调节细胞铁死亡来干预相关疾病的发生发展已成为病因学研究和治疗的热点和热点。
有效诱导铁死亡可显著抑制肿瘤的生长。有报道指出对常规化学药物治疗耐受的肿瘤细胞对铁死亡诱导剂异常敏感。放射治疗通过激活ACSL4及增强ROS产生促进肿瘤细胞铁死亡。铁死亡介导放疗疗效的发挥。免疫治疗过程中，CD8+T细胞通过分泌IFNγ来降低肿瘤细胞SLC7A11的表达及升高ACSL4的表达，以此来诱导肿瘤细胞铁死亡，最终发挥抑制肿瘤的作用。铁死亡增强剂能显著增强铁死亡诱导剂抑制肿瘤的作用。铁死亡诱导剂（或铁死亡增强剂）能显著增强肿瘤放射治疗及免疫治疗的疗效。开发铁死亡诱导剂或铁死亡增强剂具有重要的临床价值。
Tubastatin A（CAS号：1252003-15-8）是有效的，特异的组蛋白去乙酰化酶类型I和II(HDAC class I/II)抑制剂，对HDAC的IC50值为1.8 nM。对其选择性是HDAC8外的其他亚型的1000多倍。Tubastatin A选择性作用于所有同工酶除了HDAC8，对所有亚型不含HDAC8，保持超过1000倍的选择性，对HDAC8具有约57倍的选择性。2.5μM TubastatinA优先诱导α-tubulin高度乙酰化。也有研究表明Tubastatin A可以用于抑制肿瘤细胞增殖。未有研究表明Tubastatin A与GPX4相关。
发明内容
本发明的目的在于克服现有技术的至少一个不足，提供Tubastatin A的新应用。
本发明所采取的技术方案是：
本发明的第一个方面，提供：
Tubastatin A在制备GPX4抑制剂中的应用。
在一些应用的实例中，用于实验动物体内的GPX4抑制。
本发明的第二个方面，提供：
Tubastatin A在制备铁死亡诱导剂中的应用。
本发明的第三个方面，提供：
Tubastatin A在制备铁死亡诱导剂的增强剂中的应用。
在一些应用的实例中，所述铁死亡诱导剂为Erastin或RSL3。
在一些应用的实例中，Tubastatin A和Erastin的摩尔混合比为（1～3）：1；Tubastatin A和RSL3的摩尔混合比为（1～2）：1。
本发明的第四个方面，提供：
Tubastatin A在制备肿瘤放疗疗效增强剂中的应用。
在一些应用的实例中，所述肿瘤为实体肿瘤。
在一些应用的实例中，所述实体肿瘤为乳腺癌。
本发明的有益效果是：
发明人利用生物素质谱实验证实Tubastatin A能与GPX4直接结合；利用细胞内外GPX4酶活性实验证实Tubastatin A能以浓度及时间依赖的方式抑制GPX4酶活性，证实Tubastatin A是强效的GPX4抑制剂。Tubastatin A这一新应用与已知应用不接近，且不容易想到。更重要的是，与其他GPX4抑制剂相比，Tubastatin A体内利用度强，能显著诱导肿瘤细胞铁死亡的发生。Tubastatin A和现有的铁死亡诱导剂Erastin及RSL3联用可强力的诱导肿瘤细胞死亡。
附图说明
图1是Tubastatin A直接抑制GPX4酶活性的实验结果，(a)（左）生物素-链霉亲和素亲和实验示意图：MDA-MB-231细胞用生物素或生物素连接的Tubastatin A处理，Tubastatin A结合的蛋白富集在链霉亲和球珠上，将球珠进行胰蛋白酶消化，随后进行LC/LC-MS/MS分析，鉴定与Tubastatin A结合的蛋白。（右）与Tubastatin A结合的蛋白质。(b)在无细胞系统中用指定浓度Tubastatin A处理试管内的GPX4蛋白。2小时后测量各组相对的GPX4酶活性。(c)在无细胞系统中用8μMTubastatin A处理试管内的GPX4蛋白指定时间后，测量各组相对的GPX4酶活性。
图2是体内Tubastatin A通过促进放疗诱导的铁死亡来显著增强放疗疗效的实验结果，(a)经图中指定处理后，将肿瘤从小鼠皮下取出并拍照记录。(b)在不同处理后，MDA-MB-231异种移植瘤的肿瘤体积。(c)在不同处理后，MDA-MB-231异种移植瘤的肿瘤重量。(d)从不同处理组小鼠中取出肿瘤，将肿瘤经一定处理后分离出肿瘤细胞，利用流式检测肿瘤细胞的脂质过氧化（脂质过氧化是铁死亡的标志）。具体处理细节：用JL Shepherd Mark I-68A照射器以10 Gy的剂量照射肿瘤。将Tubastatin A溶解在含有1%DMSO、30%聚乙二醇、1%吐温80和68%H2O的溶剂中，然后以2.5 mg/kg的剂量皮下注射给小鼠，每天一次。每天腹腔注射在PBS中稀释的Lipro-1，剂量为10mg/kg。Tubastatin A或Lipro-1在照射前给药三次，然后继续每日给药直至终点，如相应的图所示。
图3是Tubastatin A和现有的铁死亡诱导剂Erastin及RSL3联用可强力的诱导肿瘤细胞铁死亡的实验结果，(a-b)用所示化合物处理20小时的MDA-MB-231细胞中的细胞死亡(a)和脂质过氧化(b)。Tub，4μM；Erastin，2.5μM；RLS3，2.5μM；DFO，10μM；Fer-1，10μM。(c-d)用所示化合物处理24小时的MDA-MB-231细胞的细胞活力分析。Tub，4μM；Erastin，2.5μM；RLS3，2.5μM。
具体实施方式
下面结合实验，进一步说明本发明的技术方案。
为探索Tubastatin A(简称Tub)诱导肿瘤细胞发生铁死亡的分子机制，发明人将生物素与Tubastatin A相连。生物素连接的药物（biotin-Tubastatin A）或对照组（生物素未连接药物）处理乳腺癌MDA-MB-231细胞，利用链霉亲和素磁珠将与药物相互作用的蛋白富集，通过LC/LC–MS/MS质谱分析。发明人惊奇地发现GPX4可以与Tubastatin A相互作用（图 1a）。因此，发明人进一步探索Tubastatin A是否通过抑制GPX4的酶活性来诱导铁死亡。发明人用试管内实验进行验证，通过免疫共沉淀实验将MDA-MB-231细胞的内源性GPX4蛋白分离出来，在试管内用Tubastatin A处理，用Glutathione PeroxidaseAssay试剂盒检测Tubastatin A对GPX4酶活性的影响，实验结果显示，Tubastatin A以浓度及时间依赖的方式抑制肿瘤细胞GPX4的活性，甚至在纳摩尔级别即可抑制（图 1b-c）。
为了进一步验证Tubastatin A的体内利用度，及其在体内诱导铁死亡的能力。发明人将MDA-MB-231细胞接种到裸鼠皮下，然后给予裸鼠放疗和药物处理（Tubastatin A和（或）Lipro-1（铁死亡抑制剂）或DMSO）。具体处理细节：用JL Shepherd Mark I-68A照射器以10 Gy的剂量照射肿瘤。将Tubastatin A溶解在含有1%DMSO、30%聚乙二醇、1%吐温80和68%H2O的溶剂中，然后以2.5 mg/kg的剂量皮下注射给小鼠，每天一次。每天腹腔注射在PBS中稀释的Lipro-1，剂量为10mg/kg。Tubastatin A或Lipro-1在照射前给药三次，然后继续每日给药直至第12天。和发明人预期的结果一致，在体内，Tubastatin A可显著增强放疗诱导的铁死亡。Tubastatin A与放疗联用显著抑制肿瘤的生长。铁死亡抑制剂Lipro-1可逆转Tubastatin A的作用。（图 2）。以上结果显示Tubastatin A在体内通过直接靶向GPX4增强放疗诱导的肿瘤细胞铁死亡，继而显著增强放疗的疗效。
接下来，发明人进一步探讨Tubastatin A是否可以增强铁死亡诱导剂Erastin或RSL3诱导的铁死亡，结果显示，Tubastatin A与Erastin或RSL3联用时，可明显诱导MDA-MB-231细胞发生铁死亡及增强其脂质过氧化水平，这一作用可被铁死亡抑制剂ferrostatin-1和DFO所逆转。使用的药物浓度：Tubastatin A，4μM；Erastin，2.5μM；RLS3，2.5μM；DFO，10μM；Fer-1，10μM。作用时间20h（图 3）。肿瘤细胞增殖实验也得到了类似的结果，使用的药物浓度：Tubastatin A，4μM；Erastin，2.5μM；RLS3，2.5μM。作用时间24h。这些结果说明Tubastatin A和现有的铁死亡诱导剂Erastin及RSL3联用可强力的诱导肿瘤细胞死亡。
总结：
GPX4（谷胱甘肽过氧化物酶4）是肿瘤细胞抵抗铁死亡的关键蛋白。抑制GPX4能诱导肿瘤细胞铁死亡的发生。然而，现有的GPX4抑制剂体内利用度差，诱导铁死亡的能力不强。我们发现Tubastatin A是一种新型的GPX4抑制剂。与已有的GPX4抑制剂相比，Tubastatin A体内利用度强，能显著诱导肿瘤细胞铁死亡的发生。表现在小鼠动物实验中，Tubastatin A能促进放射治疗诱导的肿瘤细胞铁死亡，增强放疗疗效（见上述图 2）。且Tubastatin A和现有的铁死亡诱导剂Erastin及RSL3联用可强力的诱导肿瘤细胞死亡（见上述图 3）。这表明，Tubastatin A作为新型的GPX4抑制剂可应用于放疗增敏，或应用于与其他铁死亡诱导剂联用来抑制肿瘤。Tubastatin A有很好的成药前景。
以上是对本发明所作的进一步详细说明，不可视为对本发明的具体实施的局限。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的简单推演或替换，都在本发明的保护范围之内。
Claims (9)
1.Tubastatin A在制备GPX4抑制剂中的应用。
2.根据权利要求1所述的应用，其特征在于，用于实验动物体内的GPX4抑制。
3.Tubastatin A在制备铁死亡诱导剂中的应用。
4.Tubastatin A在制备铁死亡诱导剂的增强剂中的应用。
5.根据权利要求4所述的应用，其特征在于，所述铁死亡诱导剂为Erastin或RSL3。
6.根据权利要求5所述的应用，其特征在于，Tubastatin A和Erastin的摩尔混合比为（1～3）：1；Tubastatin A和RSL3的摩尔混合比为（1～2）：1。
7.Tubastatin A在制备肿瘤放疗疗效增强剂中的应用。
8.根据权利要求7所述的应用，其特征在于，所述肿瘤为实体肿瘤。
9.根据权利要求8所述的应用，其特征在于，所述实体肿瘤为乳腺癌。
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