WO2017000082A1 - Levonorgestrel在制备抗卵巢癌产品中的应用 - Google Patents

Levonorgestrel在制备抗卵巢癌产品中的应用 Download PDF

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WO2017000082A1
WO2017000082A1 PCT/CN2015/000477 CN2015000477W WO2017000082A1 WO 2017000082 A1 WO2017000082 A1 WO 2017000082A1 CN 2015000477 W CN2015000477 W CN 2015000477W WO 2017000082 A1 WO2017000082 A1 WO 2017000082A1
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ovarian cancer
levonorgestrel
drug
cell
preparation
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师咏勇
宋智健
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Shanghai Jiao Tong University
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Priority to US15/740,773 priority patent/US10792291B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention relates to the field of biotechnology, in particular to the application of Levonorgestrel in the preparation of anti-ovarian cancer products.
  • Tumors are the most common and serious disease that threatens human health. Developing high-efficiency anti-tumor drugs is essential to prolong the life cycle of patients. In recent years, with the rapid development of tumor genomics and molecular pharmacology, the research and development of new anti-tumor drugs have achieved good results, but due to large investment in new drug research and development, long-term bottlenecks and other bottlenecks can not be overcome, as well as genetic variation of individual tumors. Characteristics, resulting in many traditional anti-tumor drugs are not effective, new drugs are expensive, side effects are unknown.
  • Nicardipine Promethazine, Estrone, Levonorgestrel, Sunlidac, Le vonorgestrel, Etonogestrel, Levonorgestrel, Mesalazine, Indomethaci n, Sulfasalazine, Balsalazide, Irbesartan, Ibuprofen, Isoprenaline, P Entosan Polysulfate.
  • the invention provides the use of Levonorgestrel in the preparation of a product for treating ovarian cancer.
  • a second object of the invention is to provide a new use of Levonorgestrel.
  • the present invention provides the use of Levonorgestrel in the preparation of a product for inhibiting proliferation of ovarian cancer cells.
  • a third object of the invention is to provide a new use of Levonorgestrel.
  • the present invention provides the use of Levonorgestrel in the preparation of products for reducing the IC50 value of ovarian cancer cells.
  • Levonorgestrel in the treatment of ovarian cancer is also within the scope of the invention.
  • Levonorgestrel in inhibiting the proliferation of ovarian cancer cells is also within the scope of the invention.
  • Levonorgestrel as a medicament for the treatment of ovarian cancer is also within the scope of protection of the present invention.
  • Levonorgestrel as a drug for inhibiting proliferation of ovarian cancer cells is also within the scope of the present invention.
  • the ovarian cancer cell is SKOV-3.
  • the product is a drug or a kit.
  • a fourth object of the invention is to provide a product.
  • the product provided by the present invention has an active ingredient of Levonorgestrel; the product has at least one of the following functions:
  • the ovarian cancer cell is SKOV-3.
  • the product is a drug or a kit.
  • Figure 1 shows the distribution of drug-coated tablets in a 96-well culture plate.
  • the drug to be tested in the following examples is Levonorgestrel, and its chemical structural formula is as follows:
  • ovarian cancer cell line SKOV-3 human lung cancer non-small cell NCI-H1993 and human lung adenocarcinoma cell line NCI-H441 in the following examples are as follows:
  • Doxorubicin positive drug from MCE, Cat.No.HY-15142
  • SKOV-3 cells were subjected to the above method to obtain SKOV-396 well cell culture plates.
  • SKOV-3 cells the complete medium was McCOY'S 5A, the life product, 16600082, and the cell density (cells/well) was 12,000.
  • step b) Take 79 ⁇ L of the 20 mM drug to be tested, which was configured in step a), into the first well of the first row of the dilution plate, and then add 54 ⁇ L of DMSO solvent to the second to the ninth well of the first row, from the first well. Take 25 ⁇ L of the solution into the second well, mix and take 25 ⁇ L of the solution from the second well to the third well, and then push it to the ninth well, ensuring that the drug is successively subjected to a 3.16 fold dilution.
  • test drug and the positive drug loading template are shown in Figure 1, where S1208: positive drug Doxorubicin, DMSO: positive control well, Cpd 1,2,3: drug to be tested, final concentration of DMSO is 0.5% (DMSO) compatibility).
  • step 1 Take the step 1 from the incubator to prepare the SKOV-396 well cell culture plate, and add 10 ⁇ l of the above b) to the SKOV-396 well cell culture plate according to the medicinal plate type arrangement of Fig. 1 (Fig. 1).
  • the cell culture medium (10X final concentration) of the concentration drug was placed in a CO 2 incubator at 37 ° C for 72 hours to obtain a 96-well drug sieve plate of SKOV-3.
  • the final concentrations and dosing conditions of the above-mentioned drugs to be tested, the positive drug Doxorubicin and the control wells in a 96-well plate are as follows:
  • the final concentration ( ⁇ M) of the drug to be tested in the 2-10 well of FIG. 1 was: 100, 31.64557, 10.01442, 3.169112, 1.002886, 0.317369, 0.100433, 0.031783, 0.010058;
  • the final concentration ( ⁇ M) of the positive drug Doxorubicin in the 2-10 well of Figure 1 was: 30, 9.493371, 3.004326, 0.950736, 0.300866, 0.095211, 0.03013, 0.009535, 0.003017;
  • S1208 wells E1-H1 and A12-D12 in a 96-well plate: 10 ⁇ l final concentration 100 ⁇ M
  • Doxorubicin solution solvent is complete medium solution containing 0.5% DMSO
  • DMSO wells A1-D1, E12-H12 and A11-H11: 10 ⁇ l of complete medium solution containing 0.5% DMSO.
  • Levonorgestrel has a specific inhibitory effect on the proliferation of ovarian cancer cells and can be used as a drug for treating ovarian cancer.
  • Table 1 shows the IC50 values of different cells under the action of Levonorgestrel drugs.
  • the experiments of the present invention prove that the present invention performs tumor drug retargeting on the FDA and CFDA approved drug Levonorgestrel, and screens for different anti-tumor drugs according to different cell lines (tissue types) and mutation sites of the tumor.
  • Levonorgestrel is a new use of anti-ovarian cancer to achieve new use of old drugs.

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Abstract

左炔诺孕酮（Levonorgestrel）在制备治疗卵巢癌产品中的应用。左炔诺孕酮在制备抑制卵巢癌细胞增殖产品中的应用。

Description

Levonorgestrel在制备抗卵巢癌产品中的应用 技术领域
本发明涉及生物技术领域，尤其涉及一种Levonorgestrel在制备抗卵巢癌产品中的应用。
背景技术
肿瘤是威胁人类健康的最常见也是最严重的一种疾病，研发高效抗肿瘤药物对延长患者的生存周期至关重要。近年来，随着肿瘤基因组学学和分子药理学的飞速发展，新型抗肿瘤药物的研发取得了不错的成果，但由于新药研发投入大，周期长等瓶颈无法克服，以及肿瘤个体遗传变异大等特征，导致许多传统抗肿瘤药物效果不加，新药价格昂贵，副作用未明。
Barabasi AL等研究者在2011年发表于《Nature Reviews Genetics》的论文中指出，基于GWAS研究结果和互作组学(interactome)策略开展的分子网络分析有望揭示复杂疾病新的药物靶点和分子标志物，并最终形成对疾病发病机制和治疗方案全新的认识。更值得注意的是，药物重定位(drug repositioning)研究发现，GWAS研究锁定的易感基因及与其有蛋白-蛋白相互作用(protein-protein interaction,PPI)的基因更容易成为药物间接的靶点，这一发现有助于解释现有药物的作用机制并指导新药的研发。2014年，Okada Y等研究者在《Nature》上发表的论文中显示GWAS研究结果整合分析得到的类风湿性关节炎的101个易感基因中有98个目前正用于治疗类风湿性关节炎药物的直接或间接靶标，而且还通过药物重定位研究，他们还发现了数十个已获批准用于其他适应症的药物也可用于治疗类风湿性关节炎。
发明公开
本研究正是通过整合癌症组学Cosmic version72数据库的癌症基因谱Cancer Gene Census以及蛋白质相互作用STRING version 10数据库和DrugBankversion4.2中FDA批准的药物数据库，获得的候选重定位药物，对肿瘤细胞系进行筛查实验，筛选出新的抗肿瘤药物。做肿瘤细胞系筛选的候选肿瘤抑制药物见如下:
Nicardipine,Promethazine,Estrone,Levonorgestrel,Sunlidac,Le vonorgestrel,Etonogestrel,Levonorgestrel,Mesalazine,Indomethaci n,Sulfasalazine,Balsalazide,Irbesartan,Ibuprofen,Isoprenaline,P  entosan Polysulfate。
本发明的一个目的是提供Levonorgestrel的新用途。
本发明提供的Levonorgestrel在制备治疗卵巢癌产品中的应用。
本发明的第二个目的是提供Levonorgestrel的新用途。
本发明提供了Levonorgestrel在制备抑制卵巢癌细胞增殖产品中的应用。
本发明的第三个目的是提供Levonorgestrel的新用途。
本发明提供了Levonorgestrel在制备降低卵巢癌细胞IC50值产品中的应用。
Levonorgestrel在治疗卵巢癌中的应用也是本发明保护的范围；
Levonorgestrel在抑制卵巢癌细胞增殖中的应用也是本发明保护的范围。
Levonorgestrel在作为治疗卵巢癌药物中的应用也是本发明保护的范围；
Levonorgestrel在作为抑制卵巢癌细胞增殖药物中的应用也是本发明保护的范围。
上述应用中，所述卵巢癌细胞为SKOV-3。
上述应用中，所述产品为药物或试剂盒。
本发明的第四个目的是提供一种产品。
本发明提供的产品，其活性成分为Levonorgestrel；所述产品具有如下至少一种功能：
1)治疗卵巢癌；
2)抑制卵巢癌细胞增殖；
3)降低卵巢癌细胞IC50值。
上述产品中，所述卵巢癌细胞为SKOV-3。
上述产品中，所述产品为药物或试剂盒。
附图说明
图1为96孔培养板药筛药物板型分布。
图2为Levonorgestrel对卵巢癌敏感；EC50＝3.0820；IC50＝3.3366；R2＝0.9311。
实施发明的最佳方式
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例中待测药物为Levonorgestrel，其化学结构式如下：
Figure PCTCN2015000477-appb-000001
其为drug bank产品，产品目录号为DB00367。
下面实施例中的卵巢癌细胞SKOV-3、人肺癌非小细胞NCI-H1993和人肺腺癌细胞NCI-H441的出处如下：
SKOV-3ATCC HTB-77
NCI-H1993ATCC CRL-5909
NCI-H441ATCC HTB-174
下面实施例中的主要的仪器及耗材
DMSO(from Sigma,Cat.No.D4540)
96-well白色底透细胞培养板(from Corning,Cat.No.3610)
CellTiter Glo试剂盒(from Promega,Cat.No.G7573)
Doxorubicin阳性药(from MCE,Cat.No.HY-15142)
Fetal Bovine Serum(from Gibco,Cat#10099141)
100mm培养皿(from Corning,Cat#430167)
RPMI-1640medium(from Gibco,Cat#A1049101)
DMEM medium(from Gibco,Cat#11995081)
DMEM/F12medium(from Gibco,Cat#11330057)
EMEM medium(from Gibco,Cat#10370021)
Mutidrop 384细胞分液器(Thermo,Cat#5840150)
EnSpire多功能读板机(Perkin Elmer,Cat#2300-001M)
实施例1、CELLTITER-GLO检测Levonorgestrel抗卵巢癌
一、待测孔板的制备
1、细胞铺板
a)配制各个细胞所需完全培养基。
b)实验开始前，确认标记在100mm培养皿上的药筛细胞名字，培养基以及传代时间，代次等信息，确保实验无误。
c)贴壁细胞操作参考步骤d)到i),悬浮细胞操作参考步骤j)到l)。
d)无菌操作时利用真空泵吸取细胞培养基。
e)用2ml的无菌PBS溶液润洗细胞表层，再用真空泵吸出PBS废液。
f)向培养皿轻轻加入1ml 0.25％(w/v)Trypsin-0.038％(w/v)EDTA溶液消化细胞，轻轻混匀几下，溶液覆盖住细胞表层，在倒置显微镜下观察细胞消化情况，在细胞将要脱落时终止胰酶消化作用。
g)向培养皿中加入5ml 37℃预热好的完全培养基，用移液管轻轻吹打细胞，使其从培养皿底部脱落下来。
h)将此细胞悬液转移到15ml或50ml无菌离心管中，1000rpm离心5min。
i)利用真空泵无菌操作吸出上清培养基。加入5ml 37℃预热好的完全培养基重悬细胞沉淀，轻轻吹打混匀。
j)用移液管轻轻吹打细胞，使其从培养皿底部完全脱落下来。
k)将此细胞悬液转移到15ml或50ml无菌离心管中，1000rpm离心5min。
l)利用真空泵无菌操作吸出上清培养基。加入5ml 37℃预热好的完全培养基重悬细胞沉淀，轻轻吹打混匀。
m)用细胞计数仪对细胞悬液进行计数，调整细胞悬液至合适密度接板进行细胞铺板实验。
n)将SKOV-3细胞按照上述方法进行，得到SKOV-396孔细胞培养板。
SKOV-3细胞，完全培养基为McCOY'S 5A，为life产品，16600082，接板密度(cells/well)为12000。
2、待测药物Levonorgestrel配制和加药(200X终浓度):
1)待测药物Levonorgestrel母板配制
a)用DMSO将待测药物Levonorgestrel稀释到20mM待用。
b)取a)步骤中配置好的20mM待测药物79μL加入稀释板第一行第一孔中，随后加入54μL的DMSO溶剂到第一行第二孔至第九孔中，从第一孔中取25μL溶液到第二孔中，混匀后从第二孔中取25μL溶液到第三孔中，依次类推到第九孔，保证药物逐次进行3.16倍倍比梯度稀释。
2)阳性药Doxorubicin(MCE,Cat.No.HY-15142)母板配制
a)用DMSO将阳性药Doxorubicin稀释到6mM待用。
b)将6mM阳性药Doxorubicin溶液加入稀释板中，DMSO溶液1:3.16倍倍比梯度稀释该待测药物。
3、药物工作板配制及加药
a)待测药物及阳性药加样模板如下图1所示，其中，S1208:阳性药Doxorubicin,DMSO:阳性对照孔,Cpd 1,2,3:待测药物,DMSO终浓度为0.5％(DMSO兼容性)。
b)向工作板中加入95μl细胞特定的完全培养基，每个药物对应9个孔，用多道排枪从待测药物和阳性药doxorubicin母板中分别依次转移5μl一系列(9个孔)倍比稀释好的溶液(10X终浓度)，得到含有不同浓度药物的细胞培养基。
c)从培养箱中取出步骤1制备SKOV-396孔细胞培养板，按图1加药板型排列方式(图1)分别向SKOV-396孔细胞培养板中加入10μl上述b)制备的含有不同浓度药物的细胞培养基(10X终浓度)，放入到CO2培养箱37℃培养72h，得到SKOV-3的96孔药筛板。
以不加任何药物的作为对照孔。
上述待测药物、阳性药Doxorubicin和对照孔在96孔板中的终浓度及加药情况如下：
待测药物在图1的2-10孔中的终浓度(μM)依次为:100、31.64557、10.01442、3.16912、1.002886、0.317369、0.100433、0.031783、0.010058；
阳性药Doxorubicin在图1的2-10孔中的终浓度(μM)依次为:30、9.493671、3.004326、0.950736、0.300866、0.095211、0.03013、0.009535、0.003017；
此外，96孔板中S1208孔(E1-H1和A12-D12):10μl终浓度100 μM Doxorubicin溶液(溶剂为包含0.5％DMSO的完全培养基溶液),DMSO孔(A1-D1,E12-H12和A11-H11):10μl包含0.5％DMSO的完全培养基溶液。
二、CELLTITER-GLO荧光细胞活性检测系统检测
1、CellTiter-Glo试剂配制
a)使用前，将CellTiter-Glo试剂Buffer融化，平衡到室温使用。
b)使用前，将CellTiter-Glo试剂冻粉底物融化，平衡到室温使用。
c)取100ml平衡好的CellTiter-Glo Buffer加入到瓶装CellTiter-Glo试剂冻粉底物中，使其充分重悬形成酶/底物混合物，也就是所谓的CellTiter-Glo检测试剂。
d)轻轻混匀涡旋，并反复倒置获得均匀的溶液。一般来说，1分钟内CellTiter-Glo底物试剂就会充分溶解，分装，避光保存在-20℃备用，避免反复冻融。
2、检测
a)检测前，将上述一的3得到的SKOV-3的96孔药筛板在室温中平衡20-30分钟。
b)倒置显微镜观察每块培养板的细胞形态及死亡情况，标记出异常情况并复测一次。
c)向所有药筛孔中加入100μl上述1制备的CellTiter-Glo试剂，混匀。
d)在96孔微孔板振荡器上充分震荡混匀2分钟，使细胞完全裂解。
e)避光室温放置15分钟后进行冷光信号检测，保证信号的稳定性。
f)使用EnSpire多功能读板机570nm时读取冷光信号。
g)分析处理数据。
SKOV-3的96孔药筛板结果如图2所示。
计算IC50值，结果如表1所示。
采用同样的方法检测Levonorgestrel作用人肺癌非小细胞NCI-H1993和人肺腺癌细胞NCI-H441，细胞的IC50值，结果如表1。
可以看出，Levonorgestrel对卵巢癌细胞增殖具有特异抑制作用，可以用来作为治疗卵巢癌的药物。
表1为不同细胞在Levonorgestrel药物作用下的IC50值
细胞 IC50值
SKOV-3 3.3366
NCI-H441 100
NCI-H1993 100
工业应用
本发明的实验证明，本发明对FDA,CFDA已获批准的药物Levonorgestrel进行肿瘤药物重定位，根据肿瘤不同的细胞系(组织类型)以及突变位点对适应症不是抗肿瘤的药物进行筛选，发现Levonorgestrel抗卵巢癌这种新用途，实现旧药新用。

Claims (9)

  1. Levonorgestrel在制备治疗卵巢癌产品中的应用；
    或Levonorgestrel在制备抑制卵巢癌细胞增殖产品中的应用。
  2. 根据权利要求1所述的应用，其特征在于：所述卵巢癌细胞为SKOV-3；所述产品为药物或试剂盒。
  3. Levonorgestrel在治疗卵巢癌中的应用；
    或Levonorgestrel在抑制卵巢癌细胞增殖中的应用。
  4. 根据权利要求3所述的应用，其特征在于：所述卵巢癌细胞为SKOV-3。
  5. Levonorgestrel在作为治疗卵巢癌药物中的应用；
    或Levonorgestrel在作为抑制卵巢癌细胞增殖药物中的应用。
  6. 根据权利要求5所述的应用，其特征在于：所述卵巢癌细胞为SKOV-3。
  7. 一种产品，其活性成分为Levonorgestrel；所述产品具有如下1)或2)功能：
    1)治疗卵巢癌；
    2)抑制卵巢癌细胞增殖。
  8. 根据权利要求7所述的产品，其特征在于：所述卵巢癌细胞为SKOV-3。
  9. 根据权利要求7所述的产品，其特征在于：所述产品为药物或试剂盒。
PCT/CN2015/000477 2015-06-30 2015-06-30 Levonorgestrel在制备抗卵巢癌产品中的应用 Ceased WO2017000082A1 (zh)

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US15/740,773 US10792291B2 (en) 2015-06-30 2015-06-30 Applications for levonorgestrel in preparing anti-ovarian cancer products

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010044431A1 (en) * 2000-03-21 2001-11-22 Rodriguez Gustavo C. Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium
CN1349416A (zh) * 1999-05-04 2002-05-15 美国家庭用品有限公司 含有二氢吲哚衍生物和促孕药的避孕组合物
CN101181638A (zh) * 2007-11-30 2008-05-21 程定超 女性表面涂敷用避孕剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1349416A (zh) * 1999-05-04 2002-05-15 美国家庭用品有限公司 含有二氢吲哚衍生物和促孕药的避孕组合物
US20010044431A1 (en) * 2000-03-21 2001-11-22 Rodriguez Gustavo C. Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium
US20080167276A1 (en) * 2000-03-21 2008-07-10 Rodriguez Gustavo C Pharmaceutical product containing progestin, genistein, and vitamin d compound
CN101181638A (zh) * 2007-11-30 2008-05-21 程定超 女性表面涂敷用避孕剂

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