CN112023051A - 铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用 - Google Patents
铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体提供了铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用。本发明首次揭示了铁死亡诱导剂治疗碘难治性甲状腺癌的作用,为以铁死亡为靶点的碘难治性甲状腺癌的治疗提供了理论依据,为碘难治性甲状腺癌治疗药物的研发提供了新思路。
Description
技术领域
本发明涉及医药技术领域,尤其是铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用。
背景技术
甲状腺癌是内分泌系统中最常见的恶性肿瘤之一,约占全身恶性肿瘤的3%, 也是近20年来发病率增长最快的实体恶性肿瘤,年均增长6.2%。在组织学上,甲状腺癌可以分类为滤泡上皮细胞起源的乳头状癌 (Papillary Thyroid Carcinoma, PTC)、滤泡状癌(Follicular Thyroid Carcinoma, FTC)和未分化癌(Anaplastic Thyroid Carcinoma,ATC),以及来源于滤泡旁C细胞的甲状腺髓样癌(Medullary Thyroid Carcinoma, MTC)。目前,甲状腺癌的主要治疗方法有外科手术、术后放射性碘治疗和促甲状腺激素抑制治疗。传统化疗药物对甲状腺癌疗效甚微。大多数PTC和FTC分化程度较高,患者经过外科手术、术后放射性碘治疗和促甲状腺激素抑制治疗后预后良好,可长期生存。但是,临床中仍有一部分患者出现病情进展。在这些进展性局部晚期或转移性分化型甲状腺癌病灶中,有20%-50%的病灶表现出失分化的特点,病灶失去摄碘功能而无法从131I治疗手段中获益,临床上称为放射性碘难治性分化型甲状腺癌(Radioiodine-Refractory Differentiated ThyroidCancer, RR-DTC)。此类患者的平均生存期仅为3-5年,10 年生存率为10%。ATC是恶性程度最高的甲状腺癌,侵袭性强,缺乏有效的治疗方法,是致死率极高的恶性肿瘤,患者诊断后的生存时间短暂。MTC源自甲状腺滤泡旁C细胞,放射性碘治疗无效,预后较大部分分化型甲状腺癌差。鉴于分化程度较差的PTC和FTC、ATC和MTC均对目前常规的甲状腺癌治疗方法反应欠佳、预后不良,因此统称为放射性碘难治性甲状腺癌。积极寻求难治性甲状腺癌的治疗新策略对提高甲状腺癌的疗效、改善患者的生存率及生活质量具有特殊的重要性和迫切性。
铁死亡(Ferroptosis)是哥伦比亚大学知名学者Stockwell教授在研究小分子药物Erastin 杀死含有致癌基因 RAS 突变的肿瘤细胞的作用机制时被发现的。RAS 是最常见的癌基因,RAS突变的肿瘤细胞能够通过上调转铁蛋白受体 1 和下调铁蛋白的作用增加细胞内的铁含量,利用Erastin处理RAS突变的细胞,导致细胞通过一个氧化性、非凋亡和铁依赖的机制死亡。这种细胞死亡方式是一种不同于凋亡、坏死和自噬的新方式,并将这种铁依赖的死亡方式命名为“ferroptosis”。大量研究表明,RAS突变与人类甲状腺癌,特别是放射性碘难治性甲状腺癌密切相关。然而,是否可以诱导放射性碘难治性甲状腺癌发生铁死亡,以达到疾病治疗的目的,未见有相关文献报道。因此,研究诱导碘难治性甲状腺癌发生铁死亡和以铁死亡为靶点研发治疗碘难治性甲状腺癌的药物是本领域研究人员亟需解决的问题,也是本发明的核心创新点。
发明内容
针对上述情况,为克服现有技术之缺陷,本发明之目的就是提供一种铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用。
其解决方案是,铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用。
优选地,通过靶向诱导碘难治性甲状腺癌发生铁死亡,达到治疗的目的。
优选地,所述的铁死亡诱导剂优选自Erastin,RSL3,FIN56,顺铂,柳氮磺胺吡啶,索拉菲尼,青蒿琥酯,双氢青蒿素,蒿甲醚和维生素E。
优选地,所述治疗碘难治性甲状腺癌药物是含有有效剂量的铁死亡诱导剂以及任选的药学可接受的载体和/或辅料。
优选地,所述治疗碘难治性甲状腺癌药物的给药途径包括口服给药,静脉注射,肌肉注射,皮下注射,鼻腔给药,腹腔注射,舌下给药或经皮给药。
本发明的有益效果:首次发现了铁死亡诱导剂治疗碘难治性甲状腺癌的作用,为以铁死亡为靶点的碘难治性甲状腺癌的治疗提供了理论依据,为碘难治性甲状腺癌治疗药物的研发提供了新思路。
附图说明
图1为不同铁死亡诱导剂对甲状腺癌细胞活性的影响;
图2为Ferrostatin-1对铁死亡诱导剂处理后的甲状腺癌细胞活性的影响示意图;
图3为不同铁死亡诱导剂治疗碘难治性甲状腺癌21d后的各组荷瘤裸鼠照片(A);在治疗过程中,各组肿瘤体积(B)和裸鼠体重(C)变化;
图4为不同铁死亡诱导剂治疗碘难治性甲状腺癌21d后,肿瘤组织苏木精和伊红(H&E)染色图;
图5为不同铁死亡诱导剂治疗碘难治性甲状腺癌21 d后,Western blot检测各组肿瘤组织中GPX-4含量示意图。
具体实施方式
以下实施方式旨在说明本发明而不是对本发明的进一步限定。在背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
本发明所使用的主要材料包括:
Erastin,RSL-3,索拉菲尼,双氢青蒿素,Ferrostatin-1,CCK-8试剂盒,BALB/裸鼠,苏木精和伊红染液等。乳头状甲状腺癌(PTC)细胞株BCPAP和TPC1,滤泡状甲状腺癌(FTC)细胞株WRO,滤泡状甲状腺癌失分化细胞株FTC-133,未分化甲状腺癌细胞株SW1636、FB1和T351均购自ATCC,其中,BCPAP、 TPC1、SW1636和T351细胞用RPMI1640完全培养基培养,FTC-133细胞用DMEM/F12完全培养基培养,FB1细胞用DMEM完全培养基培养,WRO细胞用加有NaHCO3的WRO细胞专用培养基培养。细胞养于T25细胞培养瓶中,当细胞密度达到80-90 %时予以传代,其方法为:去掉培养基,用PBS洗2次,加入0.5 mL胰酶消化1分钟左右,等到细胞将要完全变圆时,弃掉胰酶,加入2 mL培养液终止消化,按照1:4-1:6的比例传代至T25细胞培养瓶中,再补充培养基至5 mL,置于37 oC、100%湿度和5% CO2培养箱孵育,取对数生长期的细胞进行实验。
本发明中的滤泡状甲状腺癌失分化细胞株FTC-133为放射性碘难治性分化型甲状腺癌,未分化甲状腺癌细胞株SW1636、FB1和T351也属于放射性碘难治性甲状腺癌。
实施例1:铁死亡诱导剂对不同种类甲状腺癌细胞活性的影响
将细胞接种于96孔板,每组设6个复孔。四周用PBS缓冲液(200 μL每孔)填满,预防周边效应。37℃、5 % CO2培养箱中孵育。细胞贴壁后,弃掉旧培基,加入新配Erastin、RSL-3、索拉菲尼、双氢青蒿素的培养基,200 μL每孔,培养箱中继续孵育48h。 48h后弃掉旧培基,加培养基(100 μL/孔)和CCK-8试剂(10 μL/孔),培养箱中孵育0. 5 h;450 nm波长下用酶标仪检测各孔的OD值,计算细胞活性。
如图1所示,与对照组相比,铁死亡诱导剂Erastin、RSL-3、索拉菲尼和双氢青蒿素均可显著降低乳头状甲状腺癌(PTC)细胞株BCPAP和TPC1、滤泡状甲状腺癌(FTC)细胞株WRO、滤泡状甲状腺癌失分化细胞株FTC-133以及未分化甲状腺癌细胞株SW1636、FB1和T351的细胞活性。这一结果表明,铁死亡诱导剂可诱导碘难治性甲状腺癌发生细胞死亡。
实施例2:Ferrostatin-1对铁死亡诱导剂处理的不同种类甲状腺癌细胞活性的影响
将细胞接种于96孔板,每组设6个复孔。四周用PBS缓冲液(200 μL每孔)填满,预防周边效应。37℃、5 % CO2培养箱中孵育。细胞贴壁后,弃掉旧培基,加入新配Erastin、RSL-3、索拉菲尼、双氢青蒿素的培养基,200 μL每孔,然后每空中再加入10 μL Ferrostatin-1溶液,培养箱中继续孵育48h。 48h后弃掉旧培基,加培养基(100 μL/孔)和CCK-8试剂(10 μL/孔),培养箱中孵育0. 5 h;450 nm波长下用酶标仪检测各孔的OD值,计算细胞活性。
如图2所示,铁死亡抑制剂Ferrostatin-1可以抑制不同铁死亡诱导剂处理导致的甲状腺癌细胞死亡。这一结果进一步验证了可通过诱导细胞发生铁死亡,达到治疗放射性碘难治性甲状腺癌的目的。
实施例3:铁死亡诱导剂治疗碘难治性甲状腺癌实验
选取周龄为4-5周BALB/c裸鼠,皮下接种约107个FTC-133细胞,建立甲状腺癌移植瘤模型,待肿瘤体积达到100-200 mm3时,随机分为五组,每天分别腹腔注射生理盐水、Erastin(15 mg/kg)、RSL-3(10 mg/kg)、索拉菲尼(15 mg/kg)和双氢青蒿素(20 mg/kg)。每3天监测一次荷瘤裸鼠体重和肿瘤体积大小,连续监测21d。在21 d处理裸鼠,取肿瘤组织,苏木精和伊红(H&E)染色;Western blot检测GPX-4含量变化。
如图 3所示,与对照组相比,各治疗组肿瘤体积的增长受到了明显的抑制,具有统计学意义。H&E染色分析表明,在各治疗组中肿瘤出现了明显的坏死现象(图 4);Westernblot检测结果表明,在各治疗组中GPX-4蛋白表达明显降低(图 5)。这些结果表明,在各治疗组中发生了铁死亡,可以通过诱导碘难治性甲状腺癌铁死亡达到治疗的目的。
最后应该说明的是,以上所述仅为本发明的优选实例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神和实质的基础之上所做的任何修改或改进,均属于本发明要求保护的范围。
Claims (5)
1.铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用。
2.根据权利要求1所述的铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用,其特征在于,通过靶向诱导碘难治性甲状腺癌发生铁死亡,达到治疗的目的。
3.根据权利要求1或2所述的铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用,其特征在于,所述的铁死亡诱导剂优选自Erastin,RSL3,FIN56,顺铂,柳氮磺胺吡啶,索拉菲尼,青蒿琥酯,双氢青蒿素,蒿甲醚和维生素E。
4.根据权利要求3所述的铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用,其特征在于,所述治疗碘难治性甲状腺癌药物是含有有效剂量的铁死亡诱导剂以及任选的药学可接受的载体和/或辅料。
5.根据权利要求4所述的铁死亡诱导剂在制备治疗碘难治性甲状腺癌药物中的应用,其特征在于,所述治疗碘难治性甲状腺癌药物的给药途径包括口服给药,静脉注射,肌肉注射,皮下注射,鼻腔给药,腹腔注射,舌下给药或经皮给药。
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