CN115120595B - Liproxstatin-1在制备防治白血病的药物中的应用和其药物组合物 - Google Patents
Liproxstatin-1在制备防治白血病的药物中的应用和其药物组合物 Download PDFInfo
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Abstract
本发明涉及白血病的药物领域，具体是涉及到Liproxstatin‑1在制备防治白血病的药物中的应用和其药物组合物。本发明公开了Liproxstatin‑1在制备防治白血病的药物中的应用，含有有效剂量的Liproxstatin‑1药物组合物，通过可以诱导白血病细胞发生凋亡或者发生凋亡和焦亡，可用于白血病相关疾病的救治。
Description
技术领域
本发明涉及白血病的药物领域，具体是涉及到Liproxstatin-1在制备防治白血病的药物中的应用和其药物组合物。
背景技术
白血病(leukemia)是一类起源于造血干/祖细胞的恶性克隆性异质性疾病，也是最常见的恶性肿瘤之一。白血病分为急性白血病和慢性白血病两种类型，急、慢性白血病的自然病程、治疗手段和预后均有所不同。目前来说，白血病的治疗仍以化疗为主，抗癌药物中的烷化剂(环磷酰胺)，抗代谢药(甲氨蝶呤、阿糖胞苷)，抗生素类药(阿霉素)和抗肿瘤植物药(紫杉醇)是治疗白血病的一线药物。随着对于白血病分子机制的深入研究，发现经典的化疗药物的治疗机制常与细胞周期动力学有关。例如，阿糖胞苷和环磷酰胺可以作为S期特异性药物，在S期阻碍DNA的合成；紫杉醇可以作为M期特异性药物，使肿瘤细胞的有丝分裂阻滞于M期。近年来发现的新型靶向化疗药物维奈妥拉(Venetoclax)，通过靶向BCL-2促进肿瘤细胞凋亡，在急性髓细胞白血病及慢性淋巴细胞性白血病中有较好的疗效。尽管这些化疗药物在临床上取得了巨大的成功，但是药物耐药性是无可避免和不容忽视的。因此，亟需寻找一种针对新的治疗靶点的药物。
K562白血病细胞株构建于1970年，是从一位处于慢性粒细胞白血病急变期的患者的胸水中分离建立，是应用最广泛的白血病模型之一。
凋亡是目前机制研究最透彻的一种调节性细胞死亡方式。凋亡分为内源性凋亡和外源性凋亡，caspase-3在其中起至关重要的作用。在内源性凋亡中，BCL2家族中的促凋亡蛋白(BAX，BIM，PUMA)和抗凋亡蛋白(BCL2，BCL-XL，BCL-W)共同参与调控线粒体外膜通透性，细胞色素c的释放和caspase-3的激活。外源性凋亡主要通过死亡受体启动，如肿瘤坏死因子(TNF-α)与TNFR1的结合，可以导致下游效应caspase的激活。焦亡是近年来发现的一种新型细胞死亡方式，特征在于肿胀的细胞外膜，外膜破损和DNA凝集。Gasdermin蛋白家族是调控焦亡的最重要的蛋白，除外APJK(DFNB59)，其余的gasdermins蛋白(GSDMA-E)均存在N端效应结构域，焦亡发生时，N端效应结构域会被激活。研究表明，高表达GSDME的肿瘤细胞在发生凋亡时会继发caspase-3/GSDME依赖的焦亡。相对于凋亡而言，焦亡有着诱导肿瘤细胞迅速死亡和激活抗肿瘤免疫的双重优势。
Liproxstatin-1(Lip-1)最早于2014年在小分子化合物库中被筛选出来，其作为一种铁死亡抑制剂被广泛使用，但是关于Liproxstatin-1作为有效成分，应用于白血病的治疗未见有报道。
发明内容
为了克服现有技术的不足，本发明提供Liproxstatin-1在制备防治白血病的药物中的应用和其药物组合物，通过诱导白血病细胞发生凋亡或者发生凋亡和焦亡，可用于白血病相关疾病的救治。
本发明解决其技术问题所采用的技术方案是：
本发明的第一目的是提供：Liproxstatin-1在制备防治白血病的药物中的应用；
进一步的，所述Liproxstatin-1可诱导白血病细胞发生凋亡或者发生凋亡和焦亡，来防治白血病；
进一步的，所述Liproxstatin-1可在细胞上抑制白血病细胞周期进程，抑制肿瘤细胞的复制；
进一步的，所述白血病包括急性髓细胞白血病、急性淋巴细胞白血病、成人T淋巴细胞白血病、浆细胞白血病、慢性粒细胞白血病、慢性中性粒细胞白血病、肥大细胞白血病。
本发明的第二目的是提供一种防治白血病的药物组合物，所述药物组合物包括Liproxstatin-1和/或其药学上可接受的盐、溶剂化物；
进一步的，在所述药物组合物中Liproxstatin-1的有效剂量(含量)为微摩尔级浓度，具体为10-20μmol/L。
进一步的，所述药物组合物还包括药学上可接受的载体、赋形剂、稀释剂中的任一种或多种；所述载体包括药学领域常规的稀释剂、粘合剂、湿润剂、崩解剂、吸收促进剂、润滑剂。
进一步的，所述药物组合物的剂型包括片剂、胶囊剂、丸剂、栓剂、气雾剂、口服液体制剂、颗粒剂、散剂、注射剂、糖浆剂中的任一种或多种。上述剂型可按常规工艺来进行制备。
进一步的，所述药物组合物的给药方式包括口服、注射、植入、外用、喷雾、吸入中的任一种或多种；
更进一步的，所述Liproxstatin-1药学上可接受的盐包括乙酸盐、丙酸盐、丁酸盐、草酸盐、三甲基乙酸盐、己二酸盐、藻酸盐、乳酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、马来酸盐、富马酸盐、苦味酸盐、天冬氨酸盐、葡糖酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐；上述Liproxstatin-1药学上可接受的盐，可溶解在DMSO等非质子强极性溶剂中，备成储备液，方便进行试验。
更进一步的，所述药物组合物还包括其它有效成分，所述有效成分为化疗药物或抗癌试剂、抗炎类药物或免疫刺激剂、激素类药物、小分子靶向药物、抗体药物、中药复方制剂及中药提取物和/或中药单体及其衍生物。药物组合物通过Liproxstatin-1以及联合其它有效成分，诱导白血病细胞发生凋亡或者发生凋亡和焦亡，来防治白血病。
本发明的有益效果是：
1.本发明所述的含有有效剂量的Liproxstatin-1药物组合物，通过诱导白血病细胞发生凋亡或者发生凋亡和焦亡，可用于白血病相关疾病的救治。
2.本发明所述的药物组合物，低剂量组和高剂量组均发生G1/S期阻滞，而在高剂量组中还存在G2/M阻滞，这一结果证实了liproxstatin-1可以作为细胞周期组织药物达到治疗白血病的目的。
附图说明
下面结合附图和实施例对本发明进一步说明。
图1是本发明所述Liproxstatin-1的化学结构式；
图2是本发明CCK8法检测Liproxstatin-1对白血病细胞株K562的增殖抑制情况的示意图；
图3是本发明光学显微镜、扫描电子显微镜及透射电子显微镜检测Liproxstatin-1对白血病细胞株K562的细胞形态学的改变的示意图；
图4是本发明Annexin V-FITC/PI双染法检测Liproxstatin-1对K562白血病细胞处理前后细胞凋亡率的示意图；
图5是对图4的结果分析汇总示意图；
图6是本发明末端DNA转移酶dUTP缺口末端标记法(TUNEL)检测Liproxstatin-1对K562白血病细胞处理前后DNA断裂情况示意图；
图7是图6的结果分析汇总示意图；
图8是本发明转录组二代测序检测Liproxstatin-1对K562白血病细胞处理前后TNF，GSDME，CDKN1A的基因表达水平示意图；
图9是本发明逆转录-聚合酶链反应(RT-PCR)验证Liproxstatin-1对K562白血病细胞处理前后TNF，GSDME，CDKN1A的基因表达水平示意图；
图10是本发明蛋白质印迹法(western blotting)检测Liproxstatin-1对K562白血病细胞处理前后BAX，pro-caspase-3，cleaved-caspase-3，PARP，cleaved-PARP，GSDME，N-GSDME蛋白表达水平示意图
图11是图10的结果分析汇总示意图一；
图12是图10的结果分析汇总示意图二；
图13是本发明酶联免疫吸附实验(ELISA)检测Liproxstatin-1对K562白血病细胞处理前后细胞上清液TNF-α含量示意图；
图14是本发明CCK8法检测特异性caspase-3抑制剂z-DEVD-FMK对经Liproxstatin-1处理的K562白血病细胞的细胞存活率挽救作用示意图；
图15是本发明蛋白质印迹法(western blotting)检测z-DEVD-FMK对经Liproxstatin-1处理的K562白血病细胞的N-GSDME蛋白表达变化示意图；
图16是本发明流式细胞术检测Liproxstatin-1处理前后的K562白血病细胞的细胞周期示意图；
图17是图16的结果分析汇总示意图；
图18是本发明蛋白质印迹法(western blotting)检测Liproxstatin-1对K562白血病细胞处理前后p21WAF1/CIP1蛋白表达水平示意图。
具体实施方式
为了便于本领域技术人员的理解，下面结合实施例对本发明作进一步的说明，实施方式提及的内容并非对本发明的限定。
一、原料准备：
1.K562白血病细胞株，SH-SY5Y细胞株均购于武汉普诺赛公司，并经鉴达生物科技公司进行STR身份确认正确；
2.Liproxstatin-1(CAS号：950455-15-9)购于Selleck Chemicals公司，并用DMSO配置成储备液；Z-DEVD-FMK购于MedChemExpress公司，并用DMSO配置成储备液；
3.RPMI 1640培养基(11835-030)购于赛默飞世尔科技公司；胎牛血清购于Gemini生物公司；细胞增殖及毒性检测试剂盒(CCK-8)增强型购于美仑生物公司；Annexin V-FITC/PI凋亡试剂盒，细胞周期流式检测试剂盒均购于联科生物；Fluorescein(FITC)TunelCell Apoptosis Detection Kit购于赛维尔生物公司；TNF-αELISA试剂盒购于爱博泰克(Abclonal)公司；BAX(T40051)，PARP(T40050)，Caspase-3(T4044)，β-tubulin(M30109)，山羊抗鼠、兔二抗IgG-HRP(M21003)均由艾比玛特医药科技公司馈赠；DFNA5/GSDME-N-terminal抗体(ab215191)购于Abcam公司；GSDME-N-terminal(AF4016)购于Affinity生物公司；
4.引物均由中国生工生物工程公司合成。序列如下，均为5’---3’
RPLP0-F：GCAGCATCTACAACCCTGAAG。
RPLP0-R：CACTGGCAACATTGCGGAC。
CDKN1A-F：TGTCCGTCAGAACCCATGC。
CDKN1A-R：AAAGTCGAAGTTCCATCGCTC。
TNF-F：GAGGCCAAGCCCTGGTATG。
TNF-R：CGGGCCGATTGATCTCAGC。
GSDME-F：TGCCTACGGTGTCATTGAGTT。
GSDME-R：TCTGGCATGTCTATGAATGCAAA。
二、Liproxstatin-1在K562白血病细胞株体外实验中的作用
1.细胞培养：K562白血病细胞用完全培养基(含10％胎牛血清和1％双抗的RPMI1640培养基)进行常规细胞培养，培养时采用37℃恒温、5％CO2的条件进行。
2.模型构建：取对数生长期细胞，调整细胞密度至2×105个/ml，分别用liproxstatin-1以0μmol/L，10μmol/L，20μmol/L的浓度处理24小时，分别作为对照组，低剂量组和高剂量组。在回复性实验中，将未处理的细胞作为对照组，将仅200μmol/L浓度的z-DEVD-FMK预处理3小时的细胞作为DEVD组，将仅liproxstatin-1处理12小时的细胞作为Lip-1干预组，将200μmol/L浓度的z-DEVD-FMK预处理3小时后并liproxstatin-1处理12小时的细胞作为DEVD干预Lip-1组。
3.细胞增殖抑制实验(CCK8法)：
(1)取对数生长期细胞，250g离心5分钟，弃上清，新鲜完全培养基重悬细胞，调整密度至1×105个/ml，以100μL/孔的量将上述细胞悬液接入96孔板内。
(2)取适量的liproxstatin-1母液，调整剂量后分别加入96孔板中，使得每列的药物终浓度分别为0μmol/，2μmol/，4μmol/，10μmol/，20μmol/，40μmol/L并混匀。而后，将细胞培养板置于37℃，5％CO2培养箱中培养24小时。
(3)每孔加入10μl CCK8溶液，混匀，将细胞培养板置于37℃，5％CO2培养箱中避光孵育3小时。用Varioskan LUX化学发光酶标仪测定450nm波长处的读数。
(4)细胞存活率计算公式：细胞存活率(％)＝[(药物组吸光度值–空白组吸光度值)/(对照组吸光度值–空白组吸光度值)]×100％。半抑制浓度(IC50)值得计算由GraphPad Prism7软件计算得出。
(5)实验结果：liproxstatin-1化学式如图1所示。如图2所示，liproxstatin-1剂量依赖性的抑制K562白血病细胞株的增殖，其IC50值为11.5±2.4μmol/L，证实了liproxstatin-1对白血病的治疗作用。
4.细胞形态学检查(光镜，扫描电镜，透射电镜)
(1)光镜：将对照组、低剂量组和高剂量组细胞分别置于Olympus IX71显微镜下观察。
(2)扫描电镜：用PBS洗涤对照组、低剂量组和高剂量组细胞，用2.5％戊二醛和1％锇酸中双重固定，用乙醇溶液脱水，临界点干燥器干燥，最后，将样本紧贴于导电碳膜双面胶上放入离子溅射仪样品台上进行喷金30s。在日立SU8100扫描电子显微镜下观察细胞形态。
(3)透射电镜：用PBS洗涤对照组、低剂量组和高剂量组细胞，在2.5％戊二醛和1％锇酸中双重固定，用一系列乙醇溶液脱水，再经过渗透、包埋、超薄切片和染色程序，最后使用日立HT7800透射电镜对标本进行可视化分析。
(4)实验结果：如图3中A部所示，低剂量组和高剂量组细胞中存在明显的肿胀的细胞，肿胀细胞比例以高剂量组更加明显，在此两组中还存在少量皱缩的细胞。如图3中B部所示，扫描电镜下观察到对照组K562细胞细胞膜完整，存在微绒毛，而低剂量组细胞的外膜破裂穿孔，高剂量组细胞肿胀明显且外膜明显破裂。如图3中C部所示，透射电镜下可见对照组细胞膜完整，膜周围可见丰富伪足及突起，未见明显肿胀，结构细长，细胞核呈不规则形，局部凹陷，常染色质为主，核膜完整，核周隙正常，线粒体(M)呈圆形或杆状，数量丰富，膜完整，嵴存在；低剂量组细胞细胞存在凋亡征象，细胞呈圆形，细胞膜局部破损，细胞膜外伪足退化、消失，细胞核(N)染色质高度凝集成块，呈新月状，核膜消失，细胞器数量较少，线粒体(M)数量较少，大多崩解，嵴消失；高剂量组细胞存在焦亡征象，细胞呈圆形，细胞膜局部破损，细胞核固缩，体积变小，裂解成多块，异染色质高度凝集，电子密度加深，核膜破损，胞质电子密度稀疏，细胞器数量较少，线粒体(M)数目较少，电子密度高，内质网扩张。细胞形态学检查进一步证实了liproxstatin-1能够诱导白血病细胞发生凋亡、焦亡。
5.Annexin V-FITC/PI双染法检测细胞凋亡率
(1)用PBS洗涤对照组、低剂量组和高剂量组细胞，在4℃的环境下用Annexin V-FITC和PI避光染色10min，立即用流式细胞仪分析，最后用FlowJo软件分析数据。
(2)实验结果：如图4-5所示，早期、晚期凋亡率随着liproxstatin-1剂量的增加而增加，白血病细胞总凋亡率在20μmol/L的liproxstatin-1处理24小时可达到68.9％，进一步证实了liproxstatin-1在较低的浓度即可取得较好的疗效。
6.DNA转移酶dUTP缺口末端标记法(TUNEL)检测DNA断裂情况
(1)收集对照组、低剂量组和高剂量组细胞，4％多聚甲醛固定后进行石蜡包埋，石蜡切片脱蜡至水，蛋白酶K修复，破膜后加反应液，在DAPI复染细胞核，封片，最后用尼康ECLIPSE C1正置荧光显微镜观察。
(2)实验结果：如图6-7所示，随着liproxstatin-1浓度的增高，DNA断裂情况愈严重，证实了liproxstatin-1可以诱导白血病细胞DNA的断裂。
7.转录组二代测序及逆转录-聚合酶链反应(RT-PCR)法检测TNF，GSDME，CDKN1A(p21WAF1/CIP1)的基因表达水平
(1)转录组测序：收集对照组、低剂量组和高剂量组细胞后，转录组二代测序的实施由上海天昊生物科技公司完成。
(2)RT-PCR：收集对照组、低剂量组和高剂量组细胞，加入1ml RNA extractor，冰上反复吹打重悬沉淀，冰上静置10分钟；离心：12500rpm，4℃，离心6分钟，吸取上清液体至管中；加入200ul的氯仿，静置10分钟；再次离心：12500rpm，温度为4℃，16分钟。吸取上层含有RNA的水相510ul，加入600ul异丙醇溶液，冰上静置15分钟；离心：12500rpm，4℃，12分钟，弃去上清，1ml75％乙醇，重悬沉淀，9000rpm，4℃，6分钟离心并弃上清，重复1次；室温下控干4分钟，于紫外分光光度计下测定RNA浓度及纯度。用Takara(RR047A)反转录试剂进行反转录，程序设置为37℃，15分钟；再85℃，5秒；最后4℃，+∞。用Takara(RR820A)试剂完成实时荧光定量PCR反应，PCR仪器为Applied Biosystems 7500Real-Time PCR System，相对定量计算方法2-ΔΔCq法，检测TNF，GSDME，CDKN1A基因表达量，以RPLP0的表达水平作为内参。
(3)实验结果：如图8-9所示，低剂量组和高剂量组中的TNF、GSDME、CDKN1A基因表达水平相较于对照组明显增高(*P＜0.05)，提示外源性凋亡途径、焦亡途径及细胞周期通路可能是liproxstatin-1抑制白血病细胞的作用机制。
8.蛋白质印迹法(western blotting)检测BAX，pro-caspase-3，cleaved-caspase-3，PARP，cleaved-PARP，GSDME，N-GSDME蛋白表达水平
(1)收集对照组、低剂量组和高剂量组细胞，用含蛋白酶抑制剂的RIPA裂解液裂解细胞，超声破碎仪破碎细胞后静置30分钟；离心：12500rpm，4℃，10分钟，取上清，并进行BCA蛋白定量。将SH-SY5Y蛋白裂解液作为N-GSDME蛋白表达的阳性对照。取20μg对照组、低剂量组和高剂量组蛋白，加入到预先制好的12.5％PAGE凝胶中进行电泳，再经过转膜、封闭、洗膜、一抗孵育、二抗孵育步骤，加入ECL超敏显色液后放于GelDoc XR凝胶成像分析系统扫膜，条带用ImageJ软件进行灰度值分析。
(2)实验结果：如图10-12所示，低剂量组中BAX，cleaved-caspase-3和cleaved-PARP蛋白表达水平均较对照组升高(*P＜0.05)，高剂量组BAX，cleaved-caspase-3，cleaved-PARP，GSDME，N-GSDME蛋白表达水平均较对照组显著升高(*P＜0.05)，进一步证实了低剂量liproxstatin-1可以诱导白血病细胞发生凋亡，而高剂量liproxstatin-1可以诱导白血病细胞同时发生凋亡和焦亡。
9.酶联免疫吸附实验(ELISA)检测细胞上清液TNF-α含量
(1)收集对照组、低剂量组和高剂量组的细胞上清液备用。350μL洗涤液清洗微孔板条，加入100μL不同浓度的标准品及样品，在37℃温箱中孵育2小时，洗涤液清洗微孔板，每孔加入100μL生物素偶联抗体，在37℃温箱中孵育1小时，洗涤液清洗微孔板，每孔加入100μL链霉亲和素辣根过氧化物酶，在37℃温箱中孵育0.5小时，每孔加入100μLTMB显色底物，在37℃温箱中避光孵育15分钟，加入50μL终止液，用Varioskan LUX化学发光酶标仪测定450nm波长处的读数。
(2)实验结果：如图13所示，对照组和低剂量组细胞上清中TNF-α含量低于试剂盒的检测阈值(6.9pg/ml)，因此无法检出。高剂量组细胞上清中TNF-α含量为10.2±0.96pg/ml，进一步证实了外源性凋亡途径参与liproxstatin-1诱导的白血病细胞死亡机制。
10.回复性实验CCK8法检测特异性caspase-3抑制剂z-DEVD-FMK挽救Liproxstatin-1处理后K562白血病细胞
(1)取对数生长期细胞，250g离心5分钟，弃上清，新鲜完全培养基重悬细胞，调整密度至1×105个/ml，以100μL/孔的量将上述细胞悬液接入96孔板内。取适量的liproxstatin-1，z-DEVD-FMK母液，调整剂量后分别加入96孔板中，DEVD组和DEVD干预Lip-1组先加入200μmol/L的z-DEVD-FMK预处理3小时，随后DEVD组，DEVD干预Lip-1组和Lip-1干预组均加入20μmol/L liproxstatin-1于37℃，5％CO2培养箱中培养12小时。每孔加入10μlCCK8溶液，混匀，将细胞培养板置于37℃，5％CO2培养箱中避光孵育3小时。用VarioskanLUX化学发光酶标仪测定450nm波长处的读数。细胞存活率计算公式：细胞存活率(％)＝[(药物组吸光度值–空白组吸光度值)/(对照组吸光度值–空白组吸光度值)]×100％。细胞存活率的比较用SPSS软件进行分析。
(2)实验结果：如图14所示，DEVD干预Lip-1组较Lip-1组细胞存活率明显升高，而z-DEVD-FMK是caspase-3的特异性抑制剂，这进一步证实了liproxstatin-1通过caspase-3依赖的凋亡通路抑制白血病细胞增殖。
11.回复性实验蛋白质印迹法(western blotting)检测z-DEVD-FMK降低Liproxstatin-1处理后K562白血病细胞N-GSDME蛋白表达
收集对照组、DEVD干预Lip-1组和Lip-1干预组细胞。将SH-SY5Y蛋白裂解液作为N-GSDME蛋白表达的阳性对照。其余步骤同步骤8.1。
实验结果：如图15所示，经z-DEVD-FMK预处理后的白血病细胞在liproxstatin-1作用下N-GSDME蛋白表达量较未经预处理的Lip-1干预组明显降低(*P＜0.05)，提示高剂量liproxstatin-1诱导的白血病焦亡是caspase-3/GSDME依赖的。
12.流式细胞术检测细胞周期
(1)用PBS洗涤对照组、低剂量组和高剂量组细胞，在4℃的环境下用破膜剂和DNA染色剂避光染色30min，立即用流式细胞仪分析，最后用FlowJo软件分析数据。
(2)实验结果：如图16-17所示，低剂量组和高剂量组均发生G1/S期阻滞，而在高剂量组中还存在G2/M阻滞，这一结果证实了liproxstatin-1可以作为细胞周期组织药物达到治疗白血病的目的。
13.蛋白质印迹法(western blotting)检测p21WAF1/CIP1蛋白表达水平
(1)收集对照组、低剂量组和高剂量组细胞，其余步骤同步骤8.1，所用抗体为p21WAF1/CIP1蛋白抗体。
(2)实验结果：如图18所示，低剂量组和高剂量组的p21WAF1/CIP1蛋白表达水平均较对照组明显增高(*P＜0.05)，这一结果进一步证实了liproxstatin-1诱导的白血病细胞周期阻滞依赖p21WAF1/CIP1途径。
上述实施例为本发明较佳的实现方案，除此之外，本发明还可以其它方式实现，在不脱离本发明构思的前提下任何显而易见的替换均在本发明的保护范围之内。
Claims (4)
1.Liproxstatin-1在制备防治白血病的药物中的应用。
2.根据权利要求1所述的Liproxstatin-1在制备防治白血病的药物中的应用，其特征在于，所述Liproxstatin-1诱导白血病细胞发生凋亡或者发生凋亡和焦亡，来防治白血病。
3.根据权利要求1所述的Liproxstatin-1在制备防治白血病的药物中的应用，其特征在于，所述Liproxstatin-1可在细胞上抑制白血病细胞周期进程，抑制肿瘤细胞的复制。
4.根据权利要求1所述的Liproxstatin-1在制备防治白血病的药物中的应用，其特征在于，所述白血病包括急性髓细胞白血病、急性淋巴细胞白血病、成人T淋巴细胞白血病、浆细胞白血病、慢性粒细胞白血病、慢性中性粒细胞白血病、肥大细胞白血病。
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