CN102552912A - β3肾上腺素受体阻滞剂的抗肿瘤用途 - Google Patents
β3肾上腺素受体阻滞剂的抗肿瘤用途 Download PDFInfo
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Abstract
本发明公开了β3肾上腺素受体阻滞剂和靶向β3肾上腺素受体基因的siRNA的用途。经过大量实验证实，β3肾上腺素受体是调控SIRT1、mTOR和p53的重要因子，因此β3肾上腺素受体阻滞剂和β3肾上腺素受体的siRNA可以用于制备治疗SIRT1、mTOR和p53信号通路相关疾病的药物，如恶性肿瘤、肥厚型心肌病、类风湿性关节炎和肾功能衰竭等。本发明β3肾上腺素受体阻滞剂和β3肾上腺素受体的siRNA具有广阔的应用前景。
Description
技术领域
本发明涉及信号通路领域，具体涉及β3肾上腺素受体阻滞剂在制备治疗药物中的新用途。
背景技术
人体内的β3肾上腺素受体主要表达在脂肪细胞，尤其在内脏脂肪细胞，促进脂肪分解供能。目前已发现了多种选择性作用于该受体的激动剂与阻滞剂。对于β3受体的药物研究主要基于其促脂解作用，将β3受体激动剂作为减肥药。但是，对于β3受体在恶性肿瘤的发生、发展中的地位和其潜在治疗作用，尚无相关报道。
抑癌基因TP53是调控DNA损伤修复和细胞周期的关键基因，TP53是一个衰老相关基因，其抑癌作用与衰老密切相关。它通过调节DNA的损伤、自由基生成与清除等控制细胞衰老，p53过度活跃引起干细胞早衰，p53本身的修饰是维持其功能的主要原因。大量研究表明Sirtuin 1 (SIRT1)可通过对p53的去乙酰化作用在p53介导的老化和抗肿瘤反应中发挥关键性的作用。酵母沉默信息调节因子2(Silent Information Regulator 2，SIR2)是依赖于烟酰胺腺嘌呤二核苷酸的组蛋白去乙酰化酶，SIRT1是与哺乳动物Sir2同源性最高的家族成员，SIRT1蛋白存在于哺乳动物细胞质和细胞核中，对细胞生存、衰老和氧化应激等起到十分重要的调节作用。SIRT1使p53去乙酰化，抑制其转录活性。此外SIRT1能通过募集到p53靶启动子处，导致低乙酰化核小体转录沉默。
发明内容
本发明公开了β3肾上腺素受体(adrenergic beta-3-receptor，ADRB3)是调控SIRT1，p53，mTOR, MIF和microRNA-16信号通路的重要受体。本发明公开了β3肾上腺素受体阻滞剂的用途，用于治疗与mTOR/SIRT1/p53/MIF信号通路相关的疾病，如心肌肥大、肥厚型心肌病、心肌纤维化、肺动脉高压、动脉粥样硬化和恶性肿瘤等。本发明公开了β3肾上腺素受体阻滞剂在制备抗肿瘤药物的应用。本发明人发现β3受体阻滞剂和其siRNA可以减少肿瘤及其外周脂肪组织中的SIRT1表达，导致p53乙酰化，提高p53的转录活性，增加肿瘤组织中p53，促进肿瘤细胞衰老、凋亡并阻断远处转移。β3受体阻滞剂还可通过促进自噬，减少肿瘤细胞中线粒体，抑制ATP产生。β3受体阻滞剂通过上调白血病细胞HL-60中miR-16-1和miR-15a，促进细胞凋亡。β3受体激动剂则可增加心脏、肝脏及大脑组织中SIRT1表达，减少p53，起到抗衰老作用。本发明人还发现β3受体阻滞剂减少哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)的活性，特别是抑制mTOR-Rictor复合物，促进线粒体自噬，减少ATP产生。故β3受体激动剂可以作为mTOR的激动剂，增加胰岛素的分泌量，改善胰岛素抵抗，促进新胰岛细胞的生成。
可用于本发明的β3受体阻滞剂没有特别的限制，所有能够抑制或阻滞β3受体的化合物都适用于本发明。代表性的β3受体阻滞剂的例子是(但不限于)：SR59230A，结构式见图16。以SR59230A为母核的化合物均适用于本发明。
本发明的β3受体阻滞剂的剂型和制备方法没有特别限制，可用本领域常规通用的制法制成片剂、胶囊、颗粒剂、缓释剂、注射剂等各种剂型。
本发明的β3受体阻滞剂可以作为治疗心肌肥大、心肌病、心肌纤维化、肺动脉高压、肾功能衰竭和恶性肿瘤的药物。β3受体激动剂也可以作为SIRT1的激动剂而用于抗衰老。
此外应理解，在阅读了本发明的以上描述的内容之后，本领域的技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
附图说明
图1为SR59230A增加MCF-7细胞中p53的表达；
图2为SR59230A减少MCF-7细胞中SIRT1的表达；
图3为BRL37344减少心衰大鼠心肌凋亡；
图4为BRL37344减少心肌p53、增加SIRT1；
图5为BRL37344改善心衰大鼠心功能；
图6为脂肪干细胞中β-半乳糖苷酶染色；
图7为Rictor定量PCR；
图8为mTOR定量PCR；
图9为裸鼠肿瘤生长曲线；
图10为SR59230A抑制裸鼠肿瘤；
图11为Annexin V/PI流式细胞检测图；
图12为SR59230A增加白血病细胞HL-60、K562中miR-16-1；
图13为SR59230A增加白血病细胞HL-60、K562中miR-15a；
图14为SR59230A增加白血病细胞HL-60、K562凋亡率；
图15为SR59230A增加前列腺癌细胞PC-3自噬；
图16为SR59230A结构式。
具体实施方式
以下结合实施例来进一步解释本发明，但实施例并不对本发明做任何形式的限定。
实施例1
阻滞β3受体减少MCF-7细胞中SIRT1，增加p53表达。不同浓度的SR59230A处理MCF-7细胞，24h后裂解细胞，提取总蛋白。BCA法测定蛋白浓度，取10ug蛋白，10% SDSPAGE分离后将蛋白转至PVDF膜上，用含4％脱脂牛奶的TBST(10 mmol/L Tris HC1，pH 7.5，150 mmol/L NaC1，0.1％Tween 20)封闭膜1 h，p53抗体（1∶1000），SIRT1抗体（1∶1000），4℃，孵育过夜，洗膜后用二抗孵育1 h，ECL显色，实验重复3次。Fluorchem 8900软件分析蛋白质条带的灰度值，计算目的条带与内参条带（GAPDH）的比值。结果如图1、2示，随着SR59230A浓度的增加，p53表达增加，而SIRT1逐渐减少。
实施例2
在心肌梗死大鼠模型中，兴奋β3受体可以增加心肌细胞SIRT1，并减少p53表达，改善心功能，发挥抗凋亡作用。结扎大鼠左冠状动脉前降支，造成心梗模型。腹腔注射BRL37344 1mg/kg/day，4周后做心脏b超。取心脏组织检测凋亡（tunel法）和SIRT1、p53表达（western blot）。取心脏，测量左心室重和全心重比值（LVW/BW）。结果如图3～5，BRL37344减少心肌p53，并增加SIRT1，减少心肌细胞凋亡，减少心衰大鼠LVW/BW，逆转心肌肥厚，改善心功能。
实施例3
阻滞β3受体增加脂肪干细胞中β-半乳糖苷酶，促进干细胞老化。采用BRL37344和SR59230A各10-7M的处理大鼠脂肪干细胞，24h后，多聚甲醛固定，按照β-半乳糖苷酶染色试剂盒说明染色、摄片。结果如图6所示：与SR59230A相比，BRL37344减少脂肪干细胞中β-半乳糖苷酶，说明激动脂肪干细胞的β3肾上腺素受体可以起到抗衰老作用。
实施例4
兴奋β3受体可减少心肌细胞mTOR-Rictor复合物。采用BRL37344和SR59230A各10-7M的处理大鼠心肌细胞，8h后，提取总RNA，反转录后，做定量PCR，检测mTOR和Rictor基因表达。结果如图7、8所示：与对照组相比，BRL37344减少mTOR-Rictor复合物。
实施例5
SR59230A减小MCF-7裸鼠移植瘤体积。5周龄、雌性裸鼠皮下注射107 MCF-7细胞，建立移植瘤模型。10天后，肿瘤体积约250mm3，随机分组，每组8只，治疗组给予SR59230A 100nmol/只，腹腔注射，每2天1次，连用5周；对照组给予相同体积溶剂。每次给药前后用游标卡尺测肿瘤长、宽、高，计算肿瘤体积。肿瘤生长曲线如图9所示，与对照组相比，SR59230A组裸鼠移植瘤生长缓慢，治疗结束时肿瘤体积为对照组的42.03%，抑瘤率为57.97%，相对肿瘤增殖率T/C（%）为39.8%。取肿瘤组织石蜡包埋切片和蛋白样品，免疫组化与免疫印迹测phospho-p70S6K(Thr389), phospho-4E-BP1(Thr37/46), phospho-mTOR(Ser2448)的表达。结果表明，SR59230A抑制mTOR活性，减少phospho-p70S6K、 phospho-4E-BP1、 phospho-mTOR表达。
实施例6
SR59230A和靶向β3受体的siRNA促进MCF-7乳腺癌细胞、H1975和H1299肺癌细胞的凋亡。经电脑程序从β3AR基因的DNA序列中挑选出最合理的靶序列，然后人工合成该靶序列的DNA片段，将其克隆到载体上。人源U6启动子克隆到pcDNA3/neo载体上，用来克隆shRNA的DNA片段。用lipofectin2000把质粒载体转染到细胞中48h后，siRNA在细胞内表达，Annexin V/PI双染色，流式细胞仪检测凋亡率。如图11所示，沉默β3AR后增加MCF-7细胞凋亡率（51.1±9.3% vs 19.5±4.4%，P <0.01），G1期细胞增多（72.6±4.2 % vs 38.5±3.5 %，P <0.01）。SR 59230A组凋亡率（32.0±4.9%）较对空白照组也明显增加，差异有统计学意义（P <0.01）。H1975和H1299肺癌细胞也得到类似结果，均表现为SR59230A和靶向β3受体的siRNA促进H1975和H1299凋亡
实施例7
SR59230A通过增加白血病细胞HL-60、K562中miR-16-1和miR-15a，促进细胞凋亡。采用10-7M的SR59230A的处理白血病细胞HL-60、K562，8h后，提取总microRNA，反转录后，做定量PCR，检测miR-16-1和miR-15a表达。流式细胞术检测细胞早期凋亡标记 Annexin V／PI及凋亡率。MitoTracker Red CMXRos线粒体探针检测线粒体数量，JC1测线粒体膜电位，单丹磺酰戊二胺（Monodansylcadaverine，MDC）染色测自噬体，透射电镜观察自噬体并计数，ATP试剂盒检测胞内ATP水平。结果如图12、13、14所示，同对照组相比，SR59230A明显增加HL-60、K562的miR-16-1和miR-15a表达，并增加凋亡率（*P<0.01）。SR59230A能够使HL-60、K562细胞线粒体膜电位下降，诱导线粒体自噬，减少线粒体含量，降低胞内ATP水平。
实施例8
β3受体调控线粒体自噬。采用人前列腺癌细胞PC-3，SR59230A和BRL37344各10-7M处理18h，MDC和线粒体探针MitoTracker Red CMXRos，37℃，标记20min，PBS洗3遍，共聚焦显微镜和流式细胞仪检测荧光。Western blot测LC3 
和Beclin-1。结果：SR59230A明显减少线粒体，增加自噬小体，增加LC3
和Beclin-1表达。
总结：
本发明揭示了β3肾上腺素受体的信号通路，即β3受体调控mTOR，SIRT1，p53等蛋白的表达和活性，对于肿瘤、代谢性疾病、免疫系统疾病以及衰老相关性疾病的发生、发展有重要意义。β3受体可作为治疗靶点，通过调控β3受体，治疗以上疾病。
靶向β3肾上腺素受体基因的siRNA正向序列如SEQ ID NO:1~8所示。
5'-ctggctaggttatgccaat-3' SEQ ID NO:1；
5'-cagctctcttgccccatgg-3' SEQ ID NO:2；
5'-cagctctcttgccccatgg-3' SEQ ID NO:3；
5'-taccg ccaacaccagtggg-3' SEQ ID NO:4；
5'-cgtgttcgtgacttcgctg-3' SEQ ID NO:5；
5'-ccgcgctgctgtgccttc-3' SEQ ID NO:6；
5'-ggggtgcccgcctgcggcc-3' SEQ ID NO:7；
5'-caccgggccctg tgcacct-3' SEQ ID NO: 8。
SEQ ID NO:1
Ctggctaggttatgccaat
SEQ ID NO:2
Cagctctcttgccccatgg
SEQ ID NO:3
Cagctctcttgccccatgg
SEQ ID NO:4
taccg ccaacaccagtggg
SEQ ID NO:5
Cgtgttcgtgacttcgctg
SEQ ID NO:6
Ccgcgctgctgtgccttc
SEQ ID NO:7
Ggggtgcccgcctgcggcc
SEQ ID NO:8
caccgggccctg tgcacct
Claims (10)
1.β3肾上腺素受体在调控SIRT1、mTOR和p53信号通路中的应用。
2.β3肾上腺素受体阻滞剂在制备SIRT1、SIRT3和SIRT4抑制剂中的应用。
3.β3肾上腺素受体阻滞剂在制备p53激动剂或mTOR抑制剂中的应用。
4.β3肾上腺素受体阻滞剂在制备治疗SIRT1，mTOR，p53，MIF和microRNA-16信号通路相关疾病的药物中的应用。
5.β3肾上腺素受体阻滞剂在制备治疗心肌肥大、肥厚型心肌病、心肌纤维化、肺动脉高压、阿尔茨海默病和恶性肿瘤的药物中的应用。
6.β3肾上腺素受体作为一个治疗靶点，通过检测肿瘤及周边组织的β3肾上腺素受体的数量和活性，采用阻滞β3肾上腺素受体的治疗方法来治疗肿瘤。
7.β3肾上腺素受体阻滞剂在制备肿瘤多药耐药逆转剂中的应用。
8.β3肾上腺素受体阻滞剂在制备乳腺癌、白血病、肺癌、肝癌、结肠癌、胰腺癌、前列腺癌等恶性肿瘤药物中的应用。
9.靶向β3肾上腺素受体基因的siRNA在制备乳腺癌、白血病、肺癌、肝癌、结肠癌、胰腺癌、前列腺癌恶性肿瘤药物中的应用；siRNA的正向序列如SEQ ID NO:1~8所示。
10.β3肾上腺素受体阻滞剂在制备抗动脉粥样硬化、抗冠状动脉支架内再狭窄或冠状动脉药物支架涂层药物中的应用。
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| CN103751805B (zh) * | 2014-01-23 | 2015-09-23 | 中国人民解放军第三军医大学第一附属医院 | 干扰sirt1表达试剂在制备抑制肝癌干细胞自我更新的药物中的应用 |
| CN103751806B (zh) * | 2014-01-23 | 2015-10-14 | 中国人民解放军第三军医大学第一附属医院 | 干扰sirt1表达试剂在制备抑制肝癌干细胞干性转录因子表达的试剂中的应用 |
| CN114028582A (zh) * | 2021-10-29 | 2022-02-11 | 北京大学口腔医学院 | 一种多功能免疫脂质体及其制备方法和应用 |
| CN114028582B (zh) * | 2021-10-29 | 2023-07-28 | 北京大学口腔医学院 | 一种多功能免疫脂质体及其制备方法和应用 |
| CN115105598A (zh) * | 2022-08-08 | 2022-09-27 | 中国科学技术大学 | 靶向adrb1在免疫治疗中的用途 |
| CN115105598B (zh) * | 2022-08-08 | 2023-12-05 | 中国科学技术大学 | 靶向adrb1在免疫治疗中的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2620151A1 (en) | 2013-07-31 |
| US9622996B2 (en) | 2017-04-18 |
| EP2620151B1 (en) | 2019-11-20 |
| US20130197091A1 (en) | 2013-08-01 |
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