CN113509547A - 凝血酶在预防或治疗癌症中的应用 - Google Patents
凝血酶在预防或治疗癌症中的应用 Download PDFInfo
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- CN113509547A CN113509547A CN202111037028.9A CN202111037028A CN113509547A CN 113509547 A CN113509547 A CN 113509547A CN 202111037028 A CN202111037028 A CN 202111037028A CN 113509547 A CN113509547 A CN 113509547A
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了凝血酶在预防或治疗癌症中的应用，涉及肿瘤治疗技术领域。本发明公开了凝血酶在制备用于预防或治疗癌症的药物中的应用。本发明的研究首次发现凝血酶具有诱导发生细胞铁死亡的作用，其能够介导癌细胞的调亡，具有预防或治疗癌症的潜在用途；本发明提供了凝血酶的新用途，也为癌症的治疗提供了新的药物选择和思路。
Description
技术领域
本发明要求申请号为2020114501190，申请日为2020年12月9日，发明名称为《凝血酶在预防或治疗癌症中的应用》的优先权。
本发明涉及肿瘤治疗技术领域，具体而言，涉及凝血酶在预防或治疗癌症中的应用。
背景技术
癌症的死亡率占世界总死亡率的13％左右。目前，针对诱导癌细胞程序性死亡所研制的抗肿瘤药物，在部分患者身上已出现获得性或内在性抗性，从而发生凋亡逃逸和化疗耐受。因此，研究人员需要寻找新的细胞死亡方式来清除肿瘤细胞，并且防止抗药细胞的扩增。2012年，Dixon等发现一种受调控的细胞死亡形式，其特征是铁依赖性的脂质氢过氧化物累积导致细胞致死，并将其命名为“Ferroptosis”(铁依赖性细胞程序性死亡,铁死亡)。近年来，研究发现铁死亡在肿瘤的发生发展及肿瘤耐药方面起到重要的作用。目前已发现铁死亡诱导剂(RSL3，erastin)可抑制肾癌、肝癌、卵巢癌、弥漫性大B细胞淋巴癌、头颈部癌、乳腺癌和胶质瘤癌等肿瘤生长。铁死亡抑制剂ferrostatins(Fer-1)和liproxstatins(Lip-1)通过阻断脂质氧化过程，抑制细胞发生铁死亡。因此，诱导癌细胞铁死亡可作为一种新的抗肿瘤治疗的潜在方案。
三阴性乳腺癌(ER-/PR-/Her2-,TNBC)具有高转移高侵袭的特征。因其没有激素受体不能采用内分泌治疗，成为三阴性乳腺癌治疗的难题。但最近研究发现大多数三阴性乳腺癌对铁死亡敏感。Luuika等通过对谷氨酰胺敏感性分析确定胱氨酸/谷氨酸逆转运体(xCT)可作为常见的三阴性乳腺肿瘤治疗靶点，xCT转运体在体内三分之一的三阴性乳腺癌中表达，用临床批准的抗炎药柳氮磺胺吡啶抑制xCT可降低肿瘤生长。Marcus等发现大多数三阴性乳腺癌表达酰基辅酶a合成酶长链家族成员4(ACSL4)，表达ACSL4的乳腺癌细胞对铁死亡诱导剂敏感。但目前，市面上常见的铁死亡诱导剂种类还较少，仍需要开发更多的铁死亡诱导剂以治疗相关癌症。
发明内容
本发明的目的在于提供凝血酶在预防或治疗癌症中的应用。本发明的研究首次发现凝血酶具有诱导发生细胞铁死亡的作用，其能够介导癌细胞的调亡，进而具有预防或治疗癌症的潜在用途。本发明提供了凝血酶的新用途，也为癌症的治疗提供了新的药物选择。
本发明是这样实现的：
一方面，本发明提供凝血酶在制备用于预防或治疗癌症的药物中的应用。
本发明实施例的研究内容首次发现，凝血酶具有诱导发生细胞铁死亡的作用，其能够介导细胞例如癌细胞的调亡，说明凝血酶具有预防或治疗癌症的潜在用途，基于此，凝血酶可用于制备用于预防或治疗癌症的药物。本发明为癌症的治疗提供了新的药物选择和思路。
在可选的实施方式中，所述癌症选自乳腺癌。
需要说明的是，本发明所述的癌症包括但不限于上述的癌症类型，只要将凝血酶用于任何对铁死亡敏感的癌症实现对癌症的预防或治疗都属于本发明的保护范围。
在可选的实施方式中，所述药物的剂型选自片剂、胶囊剂、软胶囊、喷雾剂、凝胶剂、凝胶吸入剂、口服剂、混悬剂、冲剂、贴剂、软膏、丸剂、散剂、注射剂、输液剂、冻干注射剂、脂质体注射剂，靶向给药注射剂、栓剂、缓释制剂和控释制剂。
需要说明的是，本发明所述的剂型包括但不限于上述剂型，本领域技术人员可以将凝血酶制备成本领域任何可以发挥疗效的药物剂型，无论何种剂型，其均属于本发明的保护范围。
在可选的实施方式中，所述凝血酶的氨基酸序列为SEQ ID NO.1或与SEQ ID NO.1具有90％以上的同源性且具有相同的生物活性功能。
SEQ ID NO.1：
MAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRVRRANTFLEEVRKGNLERECVEETCSYEEAFEALESSTATDVFWAKYTACETARTPRDKLAACLEGNCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHPGADLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVCGQDQVTVAMTPRSEGSSVNLSPPLEQCVPDRGQQYQGRLAVTTHGLPCLAWASAQAKALSKHQDFNSAVQLVENFCRNPDGDEEGVWCYVAGKPGDFGYCDLNYCEEAVEEETGDGLDEDSDRAIEGRTATSEYQTFFNPRTFGSGEADCGLRPLFEKKSLEDKTERELLESYIDGRIVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNFTENDLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIALMKLKKPVAFSDYIHPVCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERPVCKDSTRIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKYGFYTHVFRLKKWIQKVIDQFGE。
基于本领域的常识，本领域技术人员容易想到在SEQ ID NO.1的基础上进行一个或多个氨基酸的缺失、增加或替换，并维持其相同或更高的生物活性功能，这是本领域技术人员容易实现的。因此，将与SEQ ID NO.1具有90％以上的同源性且具有相同的生物活性功能的衍生凝血酶应用于癌症的预防或治疗也是属于本发明的保护范围。
在可选的实施方式中，所述凝血酶通过诱导癌细胞发生铁死亡实现对癌症的预防或治疗作用。
另一方面，本发明提供凝血酶在制备用于诱导癌细胞发生铁死亡诱导剂中的应用。
在可选的实施方式中，所述癌细胞选择乳腺癌细胞。
在可选的实施方式中，所述凝血酶的氨基酸序列为SEQ ID NO.1或与SEQ ID NO.1具有90％以上的同源性且具有相同的生物活性功能。
再一方面，本发明还提供一种预防或治疗癌症的药物的制备方法，其包括：将凝血酶作为活性成分与药学上可接受的辅料混合以制备所述药物。
在可选的实施方式中，所述凝血酶的氨基酸序列为SEQ ID NO.1或与SEQ ID NO.1具有90％以上的同源性且具有相同的生物活性功能。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1：凝血酶Thrombin(0.01-5μM)处理MDA-MB-231细胞48小时后MTT检测细胞的生存率。
图2：铁死亡抑制剂Fer-1(0-20μM)与凝血酶(Thrombin 0.5μM)同时处理48h，然后MTT检测细胞生存率；t-test(P<0.0001)。
图3：铁死亡抑制剂Lip-1(0-10μM)与凝血酶(Thrombin 0.5μM)同时处理48h，然后MTT检测细胞生存率；t-test(P<0.0001)；
图4为各处理组的肿瘤的体积变化折线图；
图5为小鼠的体重的变化折线图以及肿瘤质量统计图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
本实施例以人乳腺癌细胞MDA-MB-231(购自American type culture collection(ATCC))为例，验证凝血酶诱导癌症细胞发生铁死亡的作用。
方法：凝血酶(Thrombin0.01-5μM)处理MDA-MB-231细胞48小时，然后MTT检测细胞的生存率。铁死亡抑制剂Fer-1(0-20μM)，Lip-1(0-10μM)与凝血酶Thrombin(0.5μM)同时处理48h，然后MTT检测细胞生存率。
结果见图1-3，从图1中可以看出，凝血酶能抑制乳腺癌细胞MDA-MB-231生长。从图2中可以看出，铁死亡抑制剂Fer-1可以抑制凝血酶杀伤乳腺癌细胞，进而说明凝血酶通过铁死亡介导细胞死亡。从图3中可以看出，铁死亡抑制剂Lip-1可以抑制凝血酶杀伤细胞，进而说明凝血酶通过铁死亡介导细胞死亡。
实施例2
雌性5周大的BALB/C Nude裸鼠购买于恩斯维尔。将MDA-MB-231细胞株悬浮于冷磷酸盐缓冲盐水(PBS)中计数，将1×107MDA-MB-231细胞注射小鼠皮下。当肿瘤达到50-100mm3时，小鼠被随机分配到对照组(control)和治疗组(Thrombin)。用无菌水稀释thrombin(abcam，ab62452)。治疗组每3天皮下结瘤部位注射thrombin，剂量为1000unit/kg，直至相应数据显示的终点。每6天测量一次肿瘤体积和小鼠重量(Body weight(g))直到终点(60天)，根据体积＝长度×宽度2×1/2公式计算肿瘤体积。并在第60天的时候称量肿瘤的质量。
各处理组的肿瘤的体积变化折线图参照图4所示，图4的左图为60天时治疗组和对照组肿瘤大小直观图，右图为6，12，18，24，30，36，42，48，54，60天时，肿瘤体积变化折线图；肿瘤重量参照图5所示。
由图可知，与对照组相比，凝血酶治疗组可以显著抑制肿瘤的体积和质量，且治疗组与非治疗组的小鼠的总体重变化不大。
以上结果足以说明凝血酶具有诱导发生细胞铁死亡的作用，其能够介导癌细胞的调亡，具有预防或治疗癌症的潜在用途，例如可以用于乳腺癌、肝癌、胰腺癌、结肠癌、肺癌、头颈癌、前列腺癌和子宫内膜癌等癌症的治疗；本发明为癌症的治疗提供了新的药物选择和思路。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。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。
SEQUENCE LISTING
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Claims (10)
1.凝血酶在制备用于预防或治疗癌症的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述癌症选自乳腺癌、肝癌、胰腺癌、结肠癌、肺癌、头颈癌、前列腺癌和子宫内膜癌。
3.根据权利要求1所述的应用，其特征在于，所述药物的剂型选自片剂、胶囊剂、软胶囊、喷雾剂、凝胶剂、凝胶吸入剂、口服剂、混悬剂、冲剂、贴剂、软膏、丸剂、散剂、注射剂、输液剂、冻干注射剂、脂质体注射剂，靶向给药注射剂、栓剂、缓释制剂和控释制剂。
4.根据权利要求1-3任一项所述的应用，其特征在于，所述凝血酶的氨基酸序列为SEQID NO.1或与SEQ ID NO.1具有90％以上的同源性且具有相同的生物活性功能。
5.根据权利要求1-3任一项所述的应用，其特征在于，所述凝血酶通过诱导癌细胞发生铁死亡实现对癌症的预防或治疗作用。
6.凝血酶在制备用于诱导癌细胞发生铁死亡诱导剂中的应用。
7.根据权利要求6所述的应用，其特征在于，所述癌细胞选择乳腺癌细胞。
8.根据权利要求6或7所述的应用，其特征在于，所述凝血酶的氨基酸序列为SEQ IDNO.1或与SEQ ID NO.1具有90％以上的同源性且具有相同的生物活性功能。
9.一种预防或治疗癌症的药物的制备方法，其特征在于，其包括：将凝血酶作为活性成分与药学上可接受的辅料混合以制备所述药物。
10.根据权利要求9所述的制备方法，其特征在于，所述凝血酶的氨基酸序列为SEQ IDNO.1或与SEQ ID NO.1具有90％以上的同源性且具有相同的生物活性功能。
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