CN114699398A - 一种用于治疗肾透明细胞癌的抑制剂 - Google Patents
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Abstract
本发明公开了一种用于治疗肾透明细胞癌的抑制剂，本申请人研究结果表明，L‑蛋氨酸亚砜酰亚胺(methionine sulfoximine，MSO)以下简称MSO作为谷氨酰胺合成酶GLUL(glutamate‑ammonia ligase)的阻滞剂，具有明显抑制肾透明细胞癌生长、增殖和转移的功能，给肾透明细胞癌的治疗带来了新的希望；进一步的，L‑蛋氨酸亚砜酰亚胺联合依维莫司能够在动物水平中，有效抑制肾透明细胞癌生长和增殖的功能，且联合使用后对肾透明细胞癌生长和增殖的抑制功能更加优异，有很大的潜力可用于肾透明细胞癌的治疗。
Description
技术领域
本发明属于医药技术领域，具体涉及一种L-蛋氨酸亚砜酰亚胺作为肾透明细胞癌药物中的应用。
背景技术
肾透明细胞癌(clear cell renal cell carcinoma，ccRCC)是肾细胞癌最为常见的病理类型(70％-75％)。研究发现，约90％以上的ccRCC存在VHL异常，如突变、甲基化等，VHL(Von Hippel-Lindau)基因功能失活是ccRCC发生发展的重要分子基础。在过去几十年肾癌药物治疗中取得最大的进展是靶向VHL-HIF(缺氧诱导因子)通路下游VEGFR(血管内皮细胞生长因子受体)的药物，如舒尼替尼、索拉非尼等。这些抗血管生成药物在部分转移性肾癌中确实取得一定疗效；但是这些药物经常存在脱靶效应和刺激性毒副作用。最近研究提示靶向VHL-HIF通路导致的代谢重编程可能会成为ccRCC有潜力的治疗策略。VHL-HIF通路的过度活化导致肾癌细胞始终处于假性缺氧的环境，基于Warburg效应ccRCC中的TCA循环的中间代谢物更多地来源于谷氨酰胺的“回补”，因而对谷氨酰胺的依赖性相较于其他肿瘤更高。既往研究也发现，谷氨酰胺剥夺(glutamine deprivation)可导致ccRCC细胞生长明显受抑制，增加细胞凋亡；体内和体外的研究也表明GLS(谷氨酰胺酶)的抑制剂在ccRCC中也可达到与谷氨酰胺剥夺一样的效应，导致明显的抗肿瘤增殖作用。因而，谷氨酰胺作为重要的“能源”在肾癌发生发展中发挥重要作用，靶向谷氨酰胺代谢重编程有望成为肾癌治疗新的方向。
L-蛋氨酸亚砜酰亚胺是谷氨酰胺合成酶GLUL(glutamate-ammonia ligase)的特异性的抑制剂。GLUL是谷氨酰胺从头合成的关键酶，在ATP(腺苷三磷酸)酶依赖下催化谷氨酸和氨转化为谷氨酰胺，进而参与到谷氨酰胺池的代谢功能、促进核苷酸及脂质等合成；另一方面解除细胞内氨毒性。既往研究发现GLUL的异常表达与多种肿瘤的发生密切相关。迄今为止，尚无文献报道GLUL及其阻滞剂L-蛋氨酸亚砜酰亚胺(MSO，methioninesulfoximine，L-蛋氨酸亚砜酰亚胺)在肾透明细胞癌中的作用。
依维莫司(everolimus，EVE)是mTOR抑制剂，mTOR是一种重要的丝氨酸-苏氨酸激酶，在多种肿瘤中活性上调，既往已有研究报道肾癌中mTOR活化明显增强。依维莫司通过与胞内蛋白FKBP12结合形成抑制性的复合体mTORC1，从而抑制mTOR通路的活性。mTOR通路活性抑制可导致转录调节因子S6核糖体蛋白激酶(S6K1)和真核生物延伸因子4E-结合蛋白(4E-BP)的磷酸化下调、活性降低，从而干扰细胞周期、糖酵解等相关蛋白的翻译和合成。此外，依维莫司还可下调血管内皮生长因子(VEGF)的表达抑制血管的新生，也可通过抑制肿瘤细胞、内皮细胞、成纤维细胞、血管平滑肌细胞等多种细胞的生长和增殖。目前临床上依维莫司已用于舒尼替尼[sunitinib]或索拉非尼[sorafenib]治疗失败后的晚期肾细胞癌患者的二线治疗。但其治疗效果目前仍欠佳，联合其他药物来增敏依维莫司效果具有重要临床意义。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的主要目的在于提供L-蛋氨酸亚砜酰亚胺在肾透明细胞癌中的应用，实验证明L-蛋氨酸亚砜酰亚胺能够有效抑制肾透明细胞癌的增殖和转移。
本发明的目的是通过以下技术方案实现的：
L-蛋氨酸亚砜酰亚胺在抑制肾透明细胞癌的生长、增殖和转移的药物中的应用。
优选地，其中所述肾透明细胞癌由786-O细胞导致。
优选地，其中所述L-蛋氨酸亚砜酰亚胺的使用浓度为30mmol/L。
优选地，其中所述药物的给药途径为腹腔注射。
L-蛋氨酸亚砜酰亚胺联合所述依维莫司在抑制肾透明细胞癌的生长、增殖和转移的药物中的应用。
优选地，其中所述肾透明细胞癌由786-O细胞导致。
优选地，其中所述L-蛋氨酸亚砜酰亚胺的使用剂量为10mg/kg，所述依维莫司的使用剂量为2.5mg/kg。
优选地，其中所述L-蛋氨酸亚砜酰亚胺的给药途径为腹腔注射，所述依维莫司的给药途径为口服。
与现有技术相比，本发明至少具有以下优点：
本发明所提供的L-蛋氨酸亚砜酰亚胺在肾透明细胞癌中的应用，其通过将L-蛋氨酸亚砜酰亚胺作为GLUL的阻滞剂，通过抑制谷氨酰胺的重头合成发挥作用，具有明显抑制肾透明细胞癌生长、增殖和转移的功能。本申请扩大了L-蛋氨酸亚砜酰亚胺的应用范围，提高了其应用价值，给肾透明细胞癌的治疗或保健带来了新的希望，且以L-蛋氨酸亚砜酰亚胺为先导化合物，通过结构修饰或改造提高活性或降低副作用，还有助于进一步开发新的抗肾透明细胞癌的药物。此外，L-蛋氨酸亚砜酰亚胺联合依维莫司对转移性肾透明细胞癌有更好疗效。
附图说明
为了更清楚地说明本发明具体实施方式，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍。
图1显示了GLUL在肾透明细胞癌中高表达，与肿瘤病理分期和预后密切相关。其中A是公共数据库CPTAC中肾透明细胞癌病人标本中，癌旁和肿瘤的GLUL蛋白比较；B为公共数据库中GLUL的拷贝数变异(Copy number variation，CNV)与肾透明细胞癌预后关系；C为免疫组化检测GLUL在肾透明细胞患者芯片中表达的结果，D和E分别为GLUL表达水平与分级和预后之间关系结果；
图2显示了L-蛋氨酸亚砜酰亚胺(MSO)能够在体外细胞及organoid水平抑制肾透明细胞癌细胞系的生长及增殖。其中A为30mM的MSO处理肾透明细胞癌786-O细胞后的CCK8实验结果，B为30mM的MSO处理肾透明细胞癌786-O细胞后的克隆形成实验结果，C为30mM的MSO处理肾透明细胞癌organoid的肿瘤形成实验结果；
图3显示了L-蛋氨酸亚砜酰亚胺(MSO)在皮下接种786-O细胞移植瘤模型上具有抑制肾透明细胞癌的生长和增殖功能，同时增加依维莫司药物效果。其中A和B为小鼠皮下成瘤的肿瘤实体和肿瘤体积示意图，C和D为皮下移植瘤的体积和肿瘤重量比较；
图4显示了L-蛋氨酸亚砜酰亚胺(MSO)在PDX模型上具有抑制肾透明细胞癌的生长和增殖功能，同时增加依维莫司药物效果。其中A和B为PDX予以MSO联合依维莫司处理后结果以及体积示意图，C和D为MSO联合依维莫司处理皮下移植瘤的体积和重量比较。
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述，以下实施例只是描述性的，不是限定性的，不能以此限定本发明的保护范围。
本发明所提供的L-蛋氨酸亚砜酰亚胺在肾透明细胞癌中的应用中所述原料及试剂均可由市场购得，其中L-蛋氨酸亚砜酰亚胺的分子式为：CH3S(O)(＝NH)CH2CH2CH(NH2)CO2H，分子量为180.23，其分子结构式为：
下面结合实施例，进一步阐述本发明：
实施例1：GLUL在肾透明细胞癌(ccRCC)中高表达，与肾透明细胞癌预后密切相关。
我们利用TCGA公共数据库资源，分析了在ccRCC和癌旁组织中GLUL蛋白表达水平和拷贝数变化，以了解GLUL的表达在ccRCC中的重要作用。同时我们利用本单位(中国人民解放军陆军特色医学中心)的ccRCC组织芯片和随访数据库，分析了GLUL与ccRCC的fuhrman分级和预后的关系。
我们分析了临床蛋白质组学肿瘤分析协会(Clinical Proteomic TumorAnalysis Consortium,CPTAC)的ccRCC蛋白质组学公共数据库，发现GLUL在ccRCC原发灶内的表达水平明显高于癌旁组织，提示GLUL与ccRCC发生相关[图1A]。我们使用UCSC Xena(https://xena.ucsc.edu)，分析了TCGA中ccRCC数据库，发现GLUL的高拷贝数与更差的ccRCC临床预后相关[图1B]。此外，我们利用本中心ccRCC组织芯片行IHC发现，GLUL的表达水平与ccRCC的fuhrman分级呈正相关[图1C-1D]，结合随访数据库，发现GLUL高表达(H-score＞4)的预后更差[图1E]。
实施例2：L-蛋氨酸亚砜酰亚胺(MSO)能够在体外细胞及organoid水平抑制肾透明细胞癌细胞系的生长及增殖。
利用CCK8、克隆形成及organoid等实验检测MSO处理后细胞及organoid的生长及增殖能力。
对于CCK8实验：利用0.25％的胰酶消化786-O细胞，计数适量的细胞数用完全培养基重悬后，0.1×104加入96孔板中培养，至次日细胞完全贴壁后用CCK8培养4小时，然后在450nm波长测吸光度，即为第0天的吸光度值。分为两组(对照组DMSO 1‰，MSO组MSO 30mM)，每组5个复孔，加入对应培养基继续培养，连续4天测试吸光度。可见30mM对786-O细胞系有明显的生长抑制作用(图2A)。
对于克隆形成实验，786-O细胞计数后，取0.1×104每孔铺到六孔板，分为对照组(DMSO 1‰)及MSO组(MSO 30mM)培养14天后收取细胞染色后采图。用PBS洗3次后，多聚甲醛和甲醇分别固定10分钟，PBS冲洗3次后，结晶紫染色2分钟，干燥后采图。结果显示，MSO对786-O细胞系的生长有明显抑制作用(图2B)。
对于3D类器官培养实验，我们利用ccRCC患者新鲜肿瘤组织标本建立3D类器官培养模型，将患者肿瘤标本去除脂肪及坏死组织并剪碎成1-2毫米大小组织碎块；使用Ⅱ型胶原酶37℃消化2小时，过细胞悬液过40μm过滤网。350g，4℃离心5分钟，保留细胞沉淀；于24孔板中间铺1层Matrigel(基质)并待其固化；使用Matrigel和培养基按1ⅹ104/40μl/孔稀释细胞，将细胞悬液铺于底层Matrigel胶上，等其凝固后每孔加入500ml培养基；生长7天后，将3D类器官分为两组(对照组DMSO 1‰，MSO组MSO 30mM)，7天后采图。可见30mM对ccRCC3D类器官具有明显的生长和克隆形成抑制作用(图2C)。
实施例3：L-蛋氨酸亚砜酰亚胺(MSO)在皮下接种和PDX模型上具有抑制肾透明细胞癌的生长和增殖功能，同时增加依维莫司药物效果
利用皮下接种786-O细胞系和PDX模型检测MSO对ccRCC的生长、增殖作用，以及联合依维莫司抗肿瘤效果。
对于皮下移植瘤实验，786-O细胞系扩增后，使用PBS：基质胶1：1的比例重悬细胞，细胞浓度为5ⅹ106/100μl。选用4周龄裸鼠，于裸鼠一侧背部皮下注射100μl细胞悬液，当肿瘤体积达到约50-100mm3时给予药物处理。实验设计四组(四组初始肿瘤体积无显著性差异)，分别为对照组(DMSO 1‰，灌胃)，MSO组(10mg/kg，腹腔注射)，Everolimus组(2.5mg/kg，灌胃)和两药联用组(MSO 10mg/kg，Everolimus 2.5mg/kg)。每周测量记录2次肿瘤尺寸，当肿瘤最大径约为1.0cm时处死裸鼠。测量肿瘤尺寸和重量，计算肿瘤体积，计算公式为体积＝长*宽*宽/2。实验结果提示MSO和Everolimus均对肿瘤有抑制作用，两药联用时能更显著抑制肿瘤生长(图3A-D)。从图3A-D可以看出，未采用DMSO的裸鼠相对于单独采用MSO、或EVE的裸鼠，其肿瘤的体积和质量均大大降低，且降低幅度高达65-70％以上，而采用MSO+EVE联合药的裸鼠，其肿瘤的体积和质量则进一步降低，降低幅度相对于单独采用MSO、或EVE的裸鼠，其肿瘤的体积和质量的降低幅度为75-85％。
对于PDX实验，将ccRCC患者肿瘤组织取下后剪碎至1-2mm大小组织块。异氟烷吸入麻醉生效后，NPG小鼠取俯卧位，脊肋区脱毛。取脊肋区长约1cm切口，逐层游离筋膜和肌肉，将肾脏挤出切口。使用镊子轻柔提起肾包膜，使用眼科剪切开长约2mm切口，将剪碎后的肿瘤组织块放入肾包膜下。将肾脏还纳后腹腔，逐层关闭切口。每周手法触摸肾区，评估移植瘤生长情况。待移植瘤最大径约6-8mm处死NPG小鼠，将扩增后的肿瘤组织切碎成约2mm大小组织块，接种于NPG小鼠一侧背部皮下。每周测量肿瘤尺寸两次，当肿瘤体积达到约200mm3时给予药物处理。实验分为四组(四组初始肿瘤体积无显著性差异)，分别为对照组(DMSO1‰，灌胃)，MSO组(10mg/kg，腹腔注射)，Everolimus组(2.5mg/kg,灌胃)和两药联用组(MSO10mg/kg，Everolimus 2.5mg/kg)。当肿瘤最大径约为1.5cm时处死NPG小鼠。测量肿瘤尺寸和重量，计算肿瘤体积，计算公式为体积＝长*宽*宽/2。实验结果提示MSO和Everolimus均对肿瘤有抑制作用，两药联用时能更显著抑制肿瘤生长(图4A-D)。从图4A-D可以看出，未采用NPG小鼠相对于单独采用MSO、或EVE的裸鼠，其肿瘤的体积和质量均大大降低，且降低幅度高达50-60％以上，而采用MSO+EVE联合药的裸鼠，其肿瘤的体积和质量则进一步降低，降低幅度相对于单独采用MSO、或EVE的NPG小鼠，其肿瘤的体积和质量的降低幅度为30-50％。
本申请所提供的L-蛋氨酸亚砜酰胺在肾透明细胞癌中的应用，首次提出了谷氨酰胺合成酶GLUL(glutamate-ammonia ligase)抑制剂MSO(methionine sulfoximine，L-蛋氨酸亚砜酰亚胺)治疗肾透明细胞癌的功能，给肾透明细胞癌的治疗带来了新的希望，还有助于进一步开发新的药物或保健品，以L-蛋氨酸亚砜酰亚胺为先导化合物，通过结构修饰或改造，有望进一步提高其活性或降低副作用。
以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围，其均应涵盖在本发明的权利要求和说明书的范围当中。
Claims (8)
1.L-蛋氨酸亚砜酰亚胺在抑制肾透明细胞癌的生长、增殖和转移的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述肾透明细胞癌由786-O细胞导致。
3.根据权利要求1所述的应用，其特征在于，所述L-蛋氨酸亚砜酰亚胺的使用浓度为30mmol/L。
4.根据权利要求1所述的应用，其特征在于，所述药物的给药途径为腹腔注射。
5.L-蛋氨酸亚砜酰亚胺联合所述依维莫司在抑制肾透明细胞癌的生长、增殖和转移的药物中的应用。
6.根据权利要求5所述的应用，其特征在于，所述肾透明细胞癌由786-O细胞导致。
7.根据权利要求5所述的应用，其特征在于，所述L-蛋氨酸亚砜酰亚胺的使用剂量为10mg/kg，所述依维莫司的使用剂量为2.5mg/kg。
8.根据权利要求5所述的应用，其特征在于，所述L-蛋氨酸亚砜酰亚胺的给药途径为腹腔注射，所述依维莫司的给药途径为口服。
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