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WO2016062267A1 - 奈必洛尔在制备抑制癌症的医药组合物中的用途 - Google Patents

奈必洛尔在制备抑制癌症的医药组合物中的用途 Download PDF

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WO2016062267A1
WO2016062267A1 PCT/CN2015/092653 CN2015092653W WO2016062267A1 WO 2016062267 A1 WO2016062267 A1 WO 2016062267A1 CN 2015092653 W CN2015092653 W CN 2015092653W WO 2016062267 A1 WO2016062267 A1 WO 2016062267A1
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cancer
nebivolol
10min
use according
cells
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French (fr)
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陈丘泓
庄秀美
魏宗德
萧乃文
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Launx Biomedical Co Ltd
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Definitions

  • the present invention relates to the use of a new indication for nebivolol drugs, and more particularly to the use of a nebivolol drug for inhibiting various cancers.
  • Nebivolol is a beta-blocker. Like other beta-blockers, nebivolol is responsible for a range of cardiac and vascular problems such as hypertension and angina. Nebivolol is a drug that has long been approved by the FDA, with a large number of drug transfer and human research results.
  • nebivolol Due to the obvious differences in clinical applications, it has never been assumed that nebivolol has the potential to inhibit cancer cells.
  • cancer has long been the leading cause of death worldwide, and the number of cancer patients has increased year by year. Therefore, treating cancer has become an important issue.
  • cancer drug treatment whether it is chemotherapy or target treatment, is intended to prevent cancer cells from replicating and dividing to block the spread and spread of tumors. According to statistics, only about five out of every 10,000 new drugs can enter the first phase of clinical trials. Further, many cancer cells successively develop drug resistance, which greatly reduces the effectiveness of drug use, and ultimately leads to failure of cancer treatment. This shows that drug development has a certain degree of difficulty.
  • the present invention aims at the development of new indications for nebivolol drugs, and achieves the goal of new use of old drugs.
  • nebivolol has no or only minimal toxicity to normal cells, but nebivolol has a selective effect between tumor cells.
  • the present invention provides a use of a nebivolol drug for the preparation of a pharmaceutical composition for inhibiting cancer, wherein the drug consists of an effective amount of Nebivolol and a pharmaceutically acceptable salt.
  • the cancer is one or more of a chest-related cancer, an abdominal cavity-related cancer, an endocrine-related cancer, and a digestive tract-related cancer.
  • the cancer is an osteosarcoma-related cancer or/and a skin cancer-related cancer.
  • chest cavity related cancer refers to lung cancer
  • the abdominal cavity related cancer is bladder cancer or/and kidney cancer or/and cervical cancer.
  • the endocrine-related cancer is one or more of prostate cancer, breast cancer, and ovarian cancer.
  • the endocrine-related cancer is one or more of gastric cancer, liver cancer, colon cancer, pancreatic cancer, and tongue cancer.
  • the effective concentration of the nebivolol drug is from 20 mg/kg to 500 mg/kg per day.
  • Figure 1 shows the results of the application of nebivolol in the present invention for inhibiting cancer cell analysis.
  • Figure 2 shows the effect of nebivolol on tumor volume
  • Figure 3 shows the inhibitory effect of high-dose and low-dose nebivolol tumor growth
  • Subculture of cell lines of different cancer types including cancerous lung cancer, gastric cancer, liver cancer, rectal cancer, skin cancer, cervical cancer, prostate cancer, bladder cancer, breast cancer, blood cancer, pancreatic cancer, ovarian cancer, tongue cancer Osteosarcoma, kidney cancer, and the control group also used normal cells of kidney (HEK293 (Kidney)), fibroblast HFW (fibroblast), and lung epithelial cells BEAS-2B (Lung Epithelial) for testing (Table 1).
  • HEK293 Kidney
  • fibroblast HFW fibroblast
  • BEAS-2B Long Epithelial
  • the cells corresponding to different species should be counted with the corresponding culture solution (Table 1), and the number of cells should be calculated, and 2 ⁇ 10 6 cell numbers should be selected.
  • Table 1 the culture solution
  • the culture medium in which the cell strain was cultured was added to a volume of 10 ml, and the culture was continued for 2-3 days.
  • the cells were then counted and dispensed into 96-well plates where the number of cells per well was fixed at 3000 cells and the volume was 100 ul.
  • IC50 is the semi-inhibitory concentration (or semi-inhibition rate). It is a very important data in the indirect competition ELISA standard curve, and the standard curve is an S-shaped curve.
  • the OD value of the control group without drug addition was B0
  • the OD value of the experimental group to which the drug was added was B
  • B/B0% was called the binding rate
  • the concentration of the drug at the binding rate was 50%. It is called IC50.
  • the smaller the value of IC50 the stronger the inhibitory effect of the drug.
  • the original culture solution in the 96-well plate was aspirated, and a commercially available drug having a concentration of 10 uM and a volume of 100 ul was added to each well. After 72 hours, 100 ul of diluted WST-1 reagent was added to each well, and the dilution ratio was the culture solution and The volume ratio of WST-1 stock solution is 9:1. Finally, the total volume of each well plate is 200ul. Then, the 96-well plate is placed at 37 °C for 30-90 minutes. ELISA reader (ELISA) is used for OD450. The absorbance values were detected and the survival rate of each cancer cell line was calculated.
  • ELISA reader ELISA reader
  • bladder cancer cell lines are TSGH and T24 two cell lines (Table 3), cervical cancer cells
  • the strains were HeLa cell line and C-33A cell line (Table 4), and the kidney cancer cell line was 786-O (Table 5).
  • the results of cancer cell inhibition experiments were performed 4 times each, and the average value was calculated. as follows.
  • prostate cancer cell lines are PC-3 and LNCap two cell lines (Table 6), breast cancer cells
  • the strains were MCF7 and MDA-MB-231, respectively (Table 7)
  • the ovarian cancer cell lines were The NIH-OVCAR-3 cell line and TOV-21G (Table 8) were subjected to four cancer cell inhibition experiments, and the average values were calculated. The results are shown below.
  • the gastric cancer cell lines were AGS and MKN-45, respectively (Table 9), liver cancer cells.
  • the strains were HepG2 and Hep3B, respectively (Table 10)
  • the colorectal cancer cell lines were HCT116-wt and LoVo cell lines (Table 11)
  • the pancreatic cancer cell lines were AsPC and BxPC cell lines, respectively (Table 12).
  • the tongue cancer cell line is a SAS cell strain (Table 13), and the results of cancer cell inhibition experiments were performed 4 times each. And the average value is calculated, and the results are listed below.
  • the osteosarctic cancer cell line was U2OS cell line (Table 14)
  • the skin cancer cell lines were A375 and BCC cell lines (Table 15), each performed 4 times.
  • the cancer cells inhibited the experimental results and calculated their average values. The results are listed below.
  • the normal kidney cell line is HEK293 cell line (Table 16)
  • the normal lung epithelial cell line is BEAS-2B cell line (Table 17)
  • each done 4 times The cancer cells inhibited the experimental results and calculated their average values. The results are listed below.
  • mice Female BALB/cAnN.Cg-Foxn1nu/CrlNarl mice were used as samples (purchased from National Experimental Animal Center), weighing 21 ⁇ 1g, subcutaneously injected into breast cancer cells (MCF7) and randomly divided into cages.
  • the test drugs were divided into three groups: Normal control group, low dose (100 mg/kg/day), high dose (200 mg/kg/day). After the tumor has formed more than 100mm3, the abdominal cavity is taken every day.
  • the drug was administered by injection; the tumor size was measured twice a week, and the tumor volume was measured as follows: (L ⁇ W2); L represents the longest diameter of the tumor; W represents the shortest diameter of the tumor. (Table 19)
  • both low-dose and high-dose nebivolol have good inhibitory effects on tumors, and the weight of mice in each group did not decrease significantly during the experiment. Both the high and low doses can make the tested mice have good health without death during the treatment.
  • high and low doses of nebivolol can effectively slow down the tumor volume and simultaneously reduce the tumor volume, and the high dose of nebivolol has a better effect.

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Abstract

本发明提供奈必洛尔（Nebivolol）在制备治疗癌症的医药组合物中的用途，所述癌症包括肺癌、膀胱癌、肾脏癌、子宫颈癌、前列腺癌、乳癌、卵巢癌、胃癌、肝癌、大肠癌、胰脏癌、舌癌等。

Description

奈必洛尔药物在制备抑制癌症的医药组合物中的用途 技术领域
本发明涉及一种奈必洛尔药物的新适应症的应用，特别涉及一种奈必洛尔药物具有抑制多种癌症的用途。
背景技术
奈必洛尔(Nebivolol)为一种β-受体阻断剂，与其他β-受体阻断剂一样，奈必洛尔主治例如高血压、心绞痛等的一系列心脏及血管问题。奈必洛尔是早已被FDA所认可的用药，具有大量药物机转及人体研究成果资料。
由于临床应用上的明显差异，因此从来没有人认为奈必洛尔具有抑制癌症细胞的可能性。
癌症长期高居全球死因之首，且罹患癌症人数更是逐年攀升，因此治疗癌症俨然成为重要的课题。一般来说，癌症药物治疗无论是化学治疗或标靶治疗，目的多是让癌细胞无法复制、分裂，来阻断肿瘤的蔓延扩张。根据统计，平均每一万个新药约只有五个能够进入第一期临床试验。进一步，许多癌细胞相继产生抗药性，使药物的使用成效大幅降低，最终导致癌症治疗失败。由此可见药物开发具有一定的困难程度。
因此，如何能让癌症药物的快速的可以被开发出来，并且尽可能的减少临床失败的机率，在癌症病学上是一个非常急迫又重要的课题。
发明内容
为解决上述的问题，本发明针对奈必洛尔药物进行新适应症的研发，而达到老药新用的目标。
经过实验设计结果显示奈必洛尔药物对正常细胞没有或仅有微小的毒性，但奈必洛尔在肿瘤细胞之间具有选择性的影响。
本发明提供一种奈必洛尔药物在制备抑制癌症的医药组合物中的用途，其中所述药物由有效剂量的奈必洛尔药物(Nebivolol)及药学上可接受的盐类所组成。
本发明一实施例中，其中所述癌症为胸腔相关癌症、腹腔相关癌症、内分泌相关癌症、消化道相关癌症中的一种或多种。
本发明一实施例中，其中所述癌症为骨肉瘤相关癌症或/和皮肤癌相关癌症。
本发明一实施例中，其中所述胸腔相关癌症指的是肺癌。
本发明一实施例中，其中所述腹腔相关癌症为膀胱癌或/和肾脏癌或/和子宫颈癌。
本发明一实施例中，其中所述内分泌相关癌症为前列腺癌、乳癌、卵巢癌中的一种或多种。
本发明一实施例中，其中所述内分泌相关癌症为胃癌、肝癌、大肠癌、胰脏癌、舌癌中的一种或多种。
本发明一实施例中，其中所述奈必洛尔药物的有效剂量浓度为每日20mg/kg～500mg/kg。
附图说明
图1为本发明奈必洛尔用药应用于抑制癌细胞分析结果。
图2显示奈必洛尔用药可对肿瘤体积的效果
图3显示高剂量及低剂量奈必洛尔肿瘤生长的抑制效果
具体实施方式
各种癌症细胞株建立
将不同癌症类型的细胞株进行继代培养，癌症细胞种类包含肺癌、胃癌、肝癌、直肠癌、皮肤癌、子宫颈癌、前列腺癌、膀胱癌、乳癌、血癌、胰腺癌、卵巢癌、舌癌、骨肉瘤、肾脏癌，并且对照组亦使用肾脏(HEK293(Kidney))、纤维母细胞HFW(fibroblast)、肺部上皮细胞BEAS-2B(Lung Epithelial)的正常细胞做测试(表一)。
先将各细胞于培养液培养后，由于各细胞的属性不同，因此针对不同种的细胞也要用相对应的培养液(表一)，计算细胞数目，选取2×106个细胞数再置入培养皿中，然后加入培养该细胞株的培养液补至体积为10ml，继续培养2-3天。之后将细胞计数，并分装至96孔盘，其中每孔的细胞数目固定为3000个细胞，且体积为100ul。
IC50即半抑制浓度(或称半抑制率)。在间接竞争ELISA标准曲线中是一个非常重要的数据，标准曲线是一个S型曲线。ICELISA中，不添加药物的对照组的OD值定为B0，添加了药物的实验组的OD值为B，B/B0％就叫做结合率，在结合率为50％时所对应的药物的浓度就叫做IC50。一般IC50的数值越小表示药物的抑制效果越强。
表一、癌症测试细胞株及其培养所用的培养液
Figure PCTCN2015092653-appb-000001
Figure PCTCN2015092653-appb-000002
细胞存活分析方法
将96孔盘中原有的培养液吸掉，每孔加入浓度10uM、体积100ul的市售药物，放置72小时后，每孔再加入100ul已稀释的WST-1试剂，该稀释比例为培养液与WST-1原液的体积比为9：1，最后每个孔盘的总体积为200ul，然后将96孔盘放置于37℃，30～90分钟，利用ELISA reader(酶联免疫检测仪)于OD450侦测吸光值，并计算各癌症细胞株的存活率。
奈必洛尔药对于各种癌细胞分析结果
奈必洛尔对胸腔相关癌症细胞抑制效果的测试
本分析奈必洛尔对胸腔相关癌症细胞抑制效果的测试，主要针对两种肺癌细胞进行测试，癌细胞株分别为A549和H1650两个细胞株，各做4次的癌细胞抑制实验结果，并且计算其平均值，结果如表二。
表二、奈必洛尔对肺癌相关癌症细胞抑制测试
  0524-10min 0526-10min 0529-10min 0531-10min 平均
A549 37.7 60.6 42.1 55.4 49.0
  1-10min 2-20min 3-20min 4-20min 平均
H1650 82.8 69.2 93.0 104.5 87.4
奈必洛尔对腹腔相关癌症细胞抑制效果的测试
本分析奈必洛尔对腹腔相关癌症细胞抑制效果的测试，主要针对两种腹腔相关癌症种类细胞进行测试，膀胱癌细胞株分别为TSGH和T24两个细胞株(表三)，子宫颈癌细胞株分别为HeLa细胞株与C-33A细胞株(表四)，肾脏癌细胞株为786-O(表五)，各做4次的癌细胞抑制实验结果，并且计算其平均值，结果表列如下。
表三、奈必洛尔对膀胱癌相关癌症细胞抑制测试
  0510-10min 0512-10min 0515-10min 0517-10min 平均
TSGH 65.5 31.8 32.5 22.3 38.0
  1-30min 2-20min 3-20min 4-20min 平均
T24 93.2 84.6 99.8 113.0 97.6
表四、奈必洛尔对子宫颈癌相关癌症细胞抑制测试
  0524-10min 0526-10min 0529-10min 0531-10min 平均
HeLa 42.9 36.9 46.8 81.4 52.0
  1 2 3 4 平均
C-33A 44.5 105.6 92.0 65.8 77.0
表五、奈必洛尔对肾脏癌相关癌症细胞抑制测试
  1 2 3 4 平均
786-O 24.6 42.1 46.4 40.2 38.3
奈必洛尔对内分泌相关癌症细胞抑制效果的测试
本分析奈必洛尔对腹腔相关癌症细胞抑制效果的测试，主要针对三种内分泌相关癌症种类细胞进行测试，前列腺癌细胞株分别为PC-3和LNCap两个细胞株(表六)，乳癌细胞株分别为MCF7和MDA-MB-231两个细胞株(表七)，卵巢癌细胞株分别为 NIH-OVCAR-3细胞株和TOV-21G(表八)，各做4次的癌细胞抑制实验结果，并且计算其平均值，结果表列如下。
表六、奈必洛尔对前列腺癌相关癌症细胞抑制测试
Figure PCTCN2015092653-appb-000003
表七、奈必洛尔对乳癌相关癌症细胞抑制测试
Figure PCTCN2015092653-appb-000004
表八、奈必洛尔对卵巢癌相关癌症细胞抑制测试
  7-3-30min 7-4-30min 7-7-30min 7-4-30min 平均
NIH-OVCAR-3 83.8 83.8 85.5 94.0 86.8
  7-3-30min 7-4-30min 7-7-30min 7-4-30min 平均
TOV-21G 99.7 79.5 90.6 74.9 86.2
奈必洛尔对消化道相关癌症细胞抑制效果的测试
分析奈必洛尔对消化道相关癌症细胞抑制效果的测试，主要针对五种消化道相关癌症种类细胞进行测试，胃癌细胞株分别为AGS和MKN-45两个细胞株(表九)，肝癌细胞株分别为HepG2和Hep3B两个细胞株(表十)，大肠癌细胞株分别为HCT116-wt和LoVo细胞株(表十一)，胰脏癌细胞株分别为AsPC和BxPC细胞株(表十二)，舌癌细胞株为SAS细胞株(表十三)，各做4次的癌细胞抑制实验结果， 并且计算其平均值，结果表列如下。
表九、奈必洛尔对胃癌相关癌症细胞抑制测试
  0510-10min 0512-10min 0515-10min 0517-10min 平均
AGS 35.1 29.5 25.8 16.1 26.6
  0510-10min 0512-10min 0515-10min 0517-10min 平均
MKN-45 58.1 59.8 43.8 49.6 52.8
表十、奈必洛尔对肝癌相关癌症细胞抑制测试
  0524-20min 0526-20min 0529-20min 0531-20min 平均
HepG2 15.3 61.1 45.0 47.0 42.1
  0612-20min 0614-20min 0616-20min 0619-20min 平均
Hep3B 42.4 49.1 38.8 49.0 44.8
表十一、奈必洛尔对大肠癌相关癌症细胞抑制测试
  0602-30min 0605-10min 0607-10min 0609-10min 平均
HCT116-wt 94.0 105.0 107.7 21.0 81.9
  0616-10min 0619-10min 0621-10min 0623-10min 平均
LoVo 89.2 70.6 81.3 100.0 85.3
表十二、奈必洛尔对胰脏癌相关癌症细胞抑制测试
  1-7-3-30min 1-7-4-30min 1-7-7-30min 1-4-30min 平均
AsPC 92.4 95.4 84.2 82.7 88.7
  3-7-3-30min 3-7-4-30min 3-7-7-30min 3-4-30min 平均
BxPC 57.0 87.5 75.8 77.3 74.4
表十三、奈必洛尔对舌癌相关癌症细胞抑制测试
  6-26-10min 6-28-10min 6-30-10min 7-3-10min 平均
SAS 80.1 87.5 67.5 67.2 75.6
奈必洛尔对其他癌症细胞抑制效果的测试
分析奈必洛尔对其他类型癌正进行测试，骨肉癌细胞株为U2OS细胞株(表十四)，皮肤癌细胞株分别为A375和BCC两个细胞株(表十五)，各做4次的癌细胞抑制实验结果，并且计算其平均值，结果表列如下。
表十四、奈必洛尔对骨肉瘤相关癌症细胞抑制测试
  6-26-10min 6-28-10min 6-30-10min 7-3-10min 平均
U2OS 66.6 56.5 76.1 67.3 66.6
表十五、奈必洛尔对皮肤癌相关癌症细胞抑制测试
  0602-30min 0605-10min 0607-10min 0609-10min 平均
A375 63.2 20.2 25.0 71.4 44.9
  0602-30min 0605-10min 0607-10min 0609-10min 平均
BCC 73.8 29.9 63.8 -- 55.8
对照组实验设计
奈必洛尔对正常细胞抑制效果的测试
分析奈必洛尔对多种正常细胞进行测试，正常肾脏细胞株为HEK293细胞株(表十六)，正常肺部上皮细胞细胞株为BEAS-2B细胞株(表十七)，各做4次的癌细胞抑制实验结果，并且计算其平均值，结果表列如下。
表十六、奈必洛尔对正常肾脏细胞抑制测试
  平均
HEK293 70.1
表十七、奈必洛尔对正常肺部上皮细胞抑制测试
  0510-10min 0512-10min 0515-10min 0517-10min 平均
BEAS-2B 53.9 66.3 75.4 73.0 67.1
针对奈必洛尔对各种癌症细胞抑制效果汇整于表十八中，清楚看出奈必洛尔对于多项癌症有明显的抑制效果。经过发明人实验结果，奈必洛尔药物对于不同的癌症细胞有明显的抑制效果。(图一)
表十八、奈必洛尔对各种癌症细胞抑制效果的汇整
癌症细胞 抑制效果
肺癌 68.19
膀胱癌 67.83
子宫颈癌 64.50
肾脏癌 38.30
前列腺癌 54.36
乳癌 46.70
卵巢癌 86.47
胃癌 39.72
肝癌 43.45
大肠癌 83.59
胰脏癌 81.54
舌癌 75.57
骨肉癌 66.64
皮肤癌 50.35
正常细胞 抑制效果
肾脏 70.10
肺部上皮细胞 67.10
动物实验分析
本实验使用雌性BALB/cAnN.Cg-Foxn1nu/CrlNarl小鼠为样本(购自国家实验动物中心)，体重为21±1g，皮下注射乳癌细胞(MCF7)后随机分笼，测试药物分成三组:正常对照组、低剂量(100mg/kg/day)、高剂量(200mg/kg/day)。肿瘤形成超过100mm3后，每天采取腹腔注 射方式给予药物；每周测量肿瘤大小两次，肿瘤体积测量公式如下：(L×W2)；L代表肿瘤最长直径；W代表肿瘤最短直径。(表十九)
Figure PCTCN2015092653-appb-000005
Figure PCTCN2015092653-appb-000006
依据第2图的结果，低剂量与高剂量的奈必洛尔均对肿瘤具有良好的抑制效果，且于实验过程中各组小鼠的重量均未出现明显降低的现象，因此表示奈必洛尔不论高低剂量在治疗过程均能使受测小鼠具有良好的健康状态而不死亡。
依据第3图的结果，高低剂量的奈必洛尔可有效减缓肿瘤体积增长，并可同时减少肿瘤体积，其中以高剂量的奈必洛尔具有较佳的效果。
上列详细说明是针对本发明之一可行实施例的具体说明，惟该实施例并非用以限制本发明的专利范围，凡未脱离本发明技艺精神所为的等效实施或变更，均应包含于本发明的专利范围中。

Claims (8)

  1. 一种奈必洛尔药物在制备抑制癌症的医药组合物中的用途，其特征是，所述医药组合物由有效剂量的奈必洛尔(Nebivolol)及药学上可接受的盐类所组成。
  2. 如权利要求1所述的用途，其特征是，所述癌症为胸腔相关癌症、腹腔相关癌症、内分泌相关癌症、消化道相关癌症中的一种或多种。
  3. 如权利要求1所述的用途，其特征是，所述癌症为骨肉瘤相关癌症或/和皮肤癌相关癌症。
  4. 如权利要求2所述的用途，其特征是，所述胸腔相关癌症为肺癌。
  5. 如权利要求2所述的用途，其特征是，所述腹腔相关癌症为膀胱癌、肾脏癌、子宫颈癌中的一种或多种。
  6. 如权利要求2所述的用途，其特征是，所述内分泌相关癌症为前列腺癌、乳癌、卵巢癌中的一种或多种。
  7. 如权利要求2所述的用途，其特征是，所述消化道相关癌症为胃癌、肝癌、大肠癌、胰脏癌、舌癌中的一种或多种。
  8. 如权利要求1所述的用途，其特征是，所述有效剂量浓度为每日20mg/kg～500mg/kg。
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PCT/CN2015/092753 Ceased WO2016062278A1 (zh) 2014-10-24 2015-10-23 内分泌疾病用药在制备抑制癌症的医药组合物中的应用
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PCT/CN2015/092702 Ceased WO2016062274A1 (zh) 2014-10-24 2015-10-23 消化系统疾病用药物在制备抑制癌症的医药组合物中的应用
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PCT/CN2015/092761 Ceased WO2016062279A1 (zh) 2014-10-24 2015-10-23 苹果酸丙氯陪拉辛锭用于制备治疗癌症药物的用途
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PCT/CN2015/092753 Ceased WO2016062278A1 (zh) 2014-10-24 2015-10-23 内分泌疾病用药在制备抑制癌症的医药组合物中的应用
PCT/CN2015/092777 Ceased WO2016062287A1 (zh) 2014-10-24 2015-10-23 山喜多药物在用于制备抑制癌症的医药组合物中的用途
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PCT/CN2015/092666 Ceased WO2016062269A1 (zh) 2014-10-24 2015-10-23 阿那格雷在用于制备治疗癌症的医药组合物中的用途
PCT/CN2015/092768 Ceased WO2016062281A1 (zh) 2014-10-24 2015-10-23 心血管疾病用药物在制备抑制癌症的医药组合物中的应用
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PCT/CN2015/092714 Ceased WO2016062275A1 (zh) 2014-10-24 2015-10-23 阿折地平在制备治疗癌症的医药组合物中的用途
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