WO2016062289A1 - 帕罗西汀药物用于制备治疗癌症的医药组合物中的用途 - Google Patents

帕罗西汀药物用于制备治疗癌症的医药组合物中的用途 Download PDF

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WO2016062289A1
WO2016062289A1 PCT/CN2015/092780 CN2015092780W WO2016062289A1 WO 2016062289 A1 WO2016062289 A1 WO 2016062289A1 CN 2015092780 W CN2015092780 W CN 2015092780W WO 2016062289 A1 WO2016062289 A1 WO 2016062289A1
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cancer
paroxetine
10min
use according
cells
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PCT/CN2015/092780
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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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朗齐生物医学股份有限公司
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Priority to US15/521,524 priority Critical patent/US20170304286A1/en
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Definitions

  • the present invention is an application of a new indication for paroxetine drugs, in particular, the use of paroxetine drugs for inhibiting various cancers.
  • 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.
  • the treatment of cancer can be divided into surgical treatment, radiation therapy, chemotherapy and target treatment.
  • cancer drug treatment is intended to prevent cancer cells from replicating and dividing to block the spread and spread of tumors.
  • cancer drugs In the design of cancer drugs, they are also designed to target high-specific drug molecules or target antibodies. According to statistics, only about five out of every 10,000 new drugs can enter the first phase of clinical trials.
  • Paroxetine (Paroxetine, fluphene, celite, paroxetine) is an option An anti-depressant of the selective serotonin reuptake inhibitor (SSRI) type, which is in the form of Paroxetine hydrochloride under the trade name "Seroxat”. It is often used clinically for the treatment of depression and obsessive-compulsive disorder.
  • SSRI selective serotonin reuptake inhibitor
  • Paroxetine is a drug that has long been approved by the FDA and has a large number of drug transfer and human research results.
  • paroxetine has the potential to inhibit cancer cells.
  • the present invention aims at the development of new indications for paroxetine drugs, and achieves the goal of new use of old drugs.
  • the present invention provides a use of a paroxetine medicament for the preparation of a pharmaceutical composition for treating cancer, wherein the pharmaceutical composition consists of an effective amount of paroxetine 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 one or more of an osteosarcoma-related cancer, a skin cancer-related cancer, and a blood cancer-related cancer.
  • the chest cavity related cancer is lung cancer.
  • the abdominal cavity-related cancer is bladder cancer or/and cervical cancer.
  • the endocrine-related cancer is prostate cancer, breast cancer, ovary One or more of cancers.
  • the endocrine-related cancer is one or more of gastric cancer, liver cancer, colon cancer, pancreatic cancer, and tongue cancer.
  • the effective dose concentration of the paroxetine drug is 20 to 500 mg/kg/day.
  • Figure 1 shows the results of the application of the paroxetine in the present invention for inhibiting cancer cell analysis.
  • 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 counted, and 2 ⁇ 10 6 cells should be returned. Then, 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 3,000 and the volume was 100 ul.
  • 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, and finally the total volume of each well plate is 200ul, then the 96-well plate is placed at 37 ° C for 30-90 minutes, using elisa The reader (enzyme-linked immunosorbent assay) detects the absorbance at OD450 and calculates the survival rate of each cancer cell line.
  • the analysis of the inhibitory effect of paroxetine on pleural cavity-related cancer cells was mainly tested on two kinds of lung cancer cells.
  • the cancer cell lines were A549 and H1650, respectively, and the results of cancer cell inhibition experiments were performed four times, and the results were calculated.
  • the average value is shown in Table 2.
  • the analysis of the inhibitory effect of paroxetine on the cells of the abdominal cavity-related cancer was mainly tested on two types of cells of the abdominal cavity-related cancer.
  • the bladder cancer cell lines were TSGH and T24, respectively (Table 3), and the cervical cancer cell lines were respectively
  • the HeLa and C-33A cell lines (Table 4)
  • the kidney cancer was the 786-O cell strain (Table 5)
  • the results of the cancer cell inhibition test were performed four times, and the average value was calculated. The results are as follows.
  • the analysis of the inhibitory effect of paroxetine on the cells of the abdominal cavity-related cancer was mainly tested against three types of endocrine-related cancer cells.
  • the prostate cancer cell lines were PC-3 and LNCap, respectively (Table 6), and the breast cancer cell lines were respectively.
  • the MCF7 and MDA-MB-231 cell lines (Table 7)
  • the ovarian cancer cell lines were NIH-OVCAR-3 cell line and TOV-21G (Table 8), respectively, and the results of cancer cell inhibition experiments were performed 4 times. And the average value is calculated, and the results are listed below.
  • mice were tested for five kinds of gastrointestinal-related cancer cell lines.
  • the gastric cancer cell lines were AGS and MKN-45, respectively (Table 9).
  • the colorectal cancer cell lines were HCT116-wt and LoVo cell lines, respectively (Table 11)
  • the pancreatic cancer cell lines were AsPC and BxPC cell lines, respectively (Table 12).
  • the tongue cancer cell line was a SAS cell strain (Table 13), and the results of the cancer cell inhibition test were performed four times each, and the average value was calculated. The results are shown below.
  • the osteosarctic cancer cell line is U2OS cell line (Table 14)
  • the skin cancer cell line is A375 and BCC two cell lines respectively (Table 15)
  • the blood cancer cell line is HL- 60 cell strains (Table 16)
  • the results of cancer cell inhibition experiments were performed 4 times each, and the average values were calculated. The results are shown 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 made 4 times of cancer The results of the cell inhibition experiments were calculated and the average values were calculated. The results are listed below.
  • paroxetine The inhibitory effect of paroxetine on various cancer cells is summarized in Table 18, and it is clear that paroxetine has a significant inhibitory effect on a number of cancers. According to the results of the inventors' experiments, the paroxetine drug has a significant inhibitory effect on different cancer cells. (Figure 1)
  • mice Female BALB/cAnN.Cg-Foxn1nu/CrlNarl mice were used as samples (purchased from National Laboratory Animal Center), weighing 21 ⁇ 1g, subcutaneously injected into gastric cancer cells (AGS) 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).
  • the tumor formed more than 100 mm 3
  • the drug was administered by intraperitoneal injection every day; the tumor size was measured twice a week, and the tumor volume measurement formula was as follows: (L ⁇ W2); L represents the longest diameter of the tumor; W represents the shortest diameter of the tumor, and its details
  • the data is as follows.
  • high and low doses of paroxetine can effectively reduce tumor volume growth and simultaneously reduce tumor volume, with high doses of paroxetine having better effects.

Abstract

一种帕罗西汀药物用于制备治疗癌症的医药组合物的用途，所述癌症为肺癌、膀胱癌、子宫颈癌、前列腺癌、乳癌、卵巢癌、胃癌、肝癌、大肠癌、胰脏癌、舌癌中的一种或多种，有效剂量为20-50mg/Kg/天。

Description

帕罗西汀药物用于制备治疗癌症的医药组合物中的用途 技术领域
本发明为帕罗西汀药物的新适应症的应用，尤其是帕罗西汀药物具有抑制多种癌症的用途。
背景技术
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。癌症的治疗可区分为手术治疗、放射线治疗、化学治疗及标靶治疗。
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。
在癌症药物的设计上也是均朝向高专一性的药物分子开发或标靶型的抗体设计，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。
此外，除了药物本身是否能大量制造的难题外，还需克服药物安全性、病人筛选、试用剂量等问题，即便药物已经通过FDA的核准并上市，还是常遇到患者对于治疗药物的反应不佳。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。
帕罗西汀(Paroxetine，氟苯哌苯醚、赛乐特、帕罗西丁)是一种选 择性5-羟色胺再吸收抑制剂(SSRI)型的抗抑郁药，其药物形态为盐酸帕罗西汀(Paroxetine hydrochloride)，商品名为「赛乐特」(Seroxat)。在临床上常用于抑郁症和强迫症的治疗。帕罗西汀是早已被FDA所认可的用药，具有大量药物机转及人体研究成果资料。
由于临床应用上的差异，因此从来没有人认为帕罗西汀具有抑制癌症细胞的可能性。
发明内容
为解决上述的问题，本发明针对帕罗西汀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，结果显示帕罗西汀药物对正常细胞没有或仅有微小的毒性。
本发明提供一种帕罗西汀药物用于制备治疗癌症的医药组合物中的用途，其中所述医药组合物是由有效剂量的帕罗西汀及药学上可接受的盐类所组成。
本发明一实施例中，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，所述癌症为骨肉瘤相关癌症、皮肤癌相关癌症、血癌相关癌症中的一种或多种。
本发明一实施例中，所述胸腔相关癌症为肺癌。
本发明一实施例中，所述腹腔相关癌症为膀胱癌或/和子宫颈癌。
本发明一实施例中，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，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，所述帕罗西汀药物的有效剂量浓度为20～500mg/kg/天。
附图说明
图1为本发明帕罗西汀用药应用于抑制癌细胞分析结果。
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，回种2×106个细胞数，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颗，且体积为100ul。
表一、癌症测试细胞株及其培养所用的培养液
Figure PCTCN2015092780-appb-000001
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。
帕罗西汀药对于各种癌细胞分析结果
帕罗西汀对胸腔相关癌症细胞抑制效果的测试
本分析帕罗西汀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，结果如表二所示。
表二、帕罗西汀对肺癌相关癌症细胞抑制测试
  0524-10min 0526-10min 0529-10min 0531-10min 平均
A549 84.19 127.41 54.01 104.12 92.43
  1-10min 2-20min 3-20min 4-20min 平均
H1650 66.4 31.6 58.2 71.3 56.9
帕罗西汀对腹腔相关癌症细胞抑制效果的测试
本分析帕罗西汀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及C-33A细胞株(表四)，腎臟癌為786-O細胞株(表五)各做4次的癌细胞抑制实验结果，并且计算其平均值，结果如下。
表三、帕罗西汀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 37.09 37.39 36.75 42.18 38.4
  1-30min 2-20min 3-20min 4-20min 平均
T24 111.7 85.2 101.5 101.5 99.9
表四、帕罗西汀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 52.61 78.32 50.99 73.36 63.82
C-33A 33.2 32.1 31.7 35.8 33.2
表五、帕羅西汀对肾脏癌相关癌症细胞抑制测试
  0524-10min 0526-10min 0529-10min 0531-10min 平均
786-O 35.2 24.0 14.6 22.3 24.0
帕罗西汀对内分泌相关癌症细胞抑制效果的测试
本分析帕罗西汀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、帕罗西汀对前列腺癌相关癌症细胞抑制测试
Figure PCTCN2015092780-appb-000002
表七、帕罗西汀对乳癌相关癌症细胞抑制测试
  0612-10min 0614-10min 0616-10min 0619-10min 平均
MCF7 47.71 49.97 55.41 51.60 51.17
  0612-10min 0614-10min 0616-10min 0619-10min 平均
MDA-MB-231 47.94 35.88 42.04 41.18 41.76
表八、帕罗西汀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 80.2 81.9 83.9 97.8 86.0
  7-3-30min 7-4-30min 7-7-30min 4-30min 平均
TOV-21G 93.5 79.7 89.2 86.1 87.1
帕罗西汀对消化道相关癌症细胞抑制效果的测试
分析帕罗西汀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、帕罗西汀对胃癌相关癌症细胞抑制测试
  0510-10min 0512-10min 0515-10min 0517-10min 平均
AGS 12.02 11.10 12.65 12.85 12.2
  0510-10min 0512-10min 0515-10min 0517-10min 平均
MKN-45 36.20 52.00 37.76 36.02 40.5
表十、帕罗西汀对肝癌相关癌症细胞抑制测试
  0524-20min 0526-20min 0529-20min 0531-20min 平均
HepG2 66.44 58.28 50.07 41.73 54.13
  0612-20min 0614-20min 0616-20min 0619-20min 平均
Hep3B 69.85 67.38 66.16 60.90 66.07
表十一、帕罗西汀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 23.78 30.62 29.66 29.47 28.38
  0616-10min 0619-10min 0621-10min 0623-10min 平均
LoVo 54.11 51.54 77.28 48.93 57.97
表十二、帕罗西汀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 78.8 87.3 69.3 72.5 77.0
  3-7-3-30min 3-7-4-30min 3-7-7-30min 3-4-30min 平均
BxPC 59.7 93.7 70.6 87.0 77.7
表十三、帕罗西汀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 48.20 26.74 57.97 73.09 51.50
帕罗西汀对其他癌症细胞抑制效果的测试
分析帕罗西汀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)，血癌细胞株为HL-60细胞株(表十六)，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、帕罗西汀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 40.61 30.75 30.29 31.10 33.19
表十五、帕罗西汀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 46.75 44.40 35.38 48.77 43.83
  0602-30min 0605-10min 0607-10min 0609-10min 平均
BCC 42.13 52.62 41.11 97.05 58.23
对照组实验设计
帕罗西汀对正常细胞抑制效果的测试
分析帕罗西汀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、帕罗西汀对正常肾脏细胞抑制测试
  0602-30min 0605-30min 0607-30min 0609-30min 平均
HEK293 64.91 76.80 76.05 67.85 71.40
表十七’、帕罗西汀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 100.97 102.64 96.40 94.56 98.64
针对帕罗西汀对各种癌症细胞抑制效果汇整于表十八中，清楚看出帕罗西汀对于多项癌症有明显的抑制效果。经过发明人实验结果，帕罗西汀药物对于不同的癌症细胞有明显的抑制效果。(图一)
表十八、帕罗西汀对各种癌症细胞抑制效果的汇整
癌症細胞 抑制效果
肺癌 74.64462204
膀胱癌 69.1
子宮頸癌 63.82
前列腺癌 44.06
乳癌 46.47
卵巢癌 86.5
胃癌 26.3
肝癌 60.10
大腸癌 43.17
胰臟癌 77.4
舌癌 51.50
骨肉癌 33.19
皮膚癌 51.03
腎臟癌 72.5
腎臟 71.40
肺部上皮細胞 98.64
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，皮下注射胃癌细胞(AGS)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，其详细数据如下所示。
表十九、帕罗西汀于动物实验对癌症对癌症的抑制效果
Figure PCTCN2015092780-appb-000003
Figure PCTCN2015092780-appb-000004
依据第2图的结果，低剂量与高剂量的帕罗西汀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，因此表示帕罗西汀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，高低剂量的帕罗西汀可有效减缓肿瘤体积增长，并可同时减少肿瘤体积，其中以高剂量的帕罗西汀具有较佳的效果。
上述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. 一种帕罗西汀药物用于制备治疗癌症的医药组合物中的用途，其特征是，所述医药组合物是由有效剂量的帕罗西汀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、皮肤癌相关癌症、血癌相关癌症中的一种或多种。
  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或/和子宫颈癌。
  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、乳癌或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、胰脏癌或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，所述有效剂量为20～500mg/kg/天。
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