CN109528728A - 甲硫达嗪在改善子宫内膜癌孕激素耐药中的应用 - Google Patents

甲硫达嗪在改善子宫内膜癌孕激素耐药中的应用 Download PDF

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CN109528728A
CN109528728A CN201811317554.9A CN201811317554A CN109528728A CN 109528728 A CN109528728 A CN 109528728A CN 201811317554 A CN201811317554 A CN 201811317554A CN 109528728 A CN109528728 A CN 109528728A
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methotrexate
progestational hormone
endometrium
endometrial carcinoma
carcinoma
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王玉东
孙笑
王晶
孟琼
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International Peace Maternity & Child Health Hospital Of China Welfare Institute
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Abstract

本发明公开了甲硫达嗪在改善子宫内膜癌孕激素耐药中的应用；所述甲硫达嗪单独使用，抑制子宫内膜癌细胞的增殖和活力；或所述甲硫达嗪与孕激素联用，促进孕激素对耐孕激素子宫内膜癌细胞的杀伤作用。本发明发现甲硫达嗪可抑制孕激素敏感/不敏感子宫内膜癌细胞的增殖与活力，对子宫内膜癌细胞的凋亡无影响；甲硫达嗪与孕激素(MPA)联合应用可进一步促进后者对孕激素敏感/不敏感子宫内膜癌细胞的抑增殖与促凋亡作用。

Description

甲硫达嗪在改善子宫内膜癌孕激素耐药中的应用
技术领域
本发明涉及药物化学，具体涉及甲硫达嗪在改善子宫内膜癌孕激素耐药中的应用。
背景技术
甲硫达嗪是一种抗精神失常药物，作用于中枢神经系统、植物神经系统和内分泌系统。文献[Sachlos E，RM，Laronde S，Shapovalova Z，Lee JH，Russell J，MaligM，McNicol JD，Fiebig-Comyn A，Graham M，Levadoux-Martin M，Lee JB，Giacomelli A，HassellJA，Fischer-Russell D，Trus MR，Foley R，Leber B，Xenocostas A，Brown ED，Collins TJ，Bhatia M.Identification of drugs including a dopamine receptorantagonist that selectively target cancer stem cells.Cell，2012.149(6)：p.1284-97.]中，曾报道甲硫达嗪可通过抑制表达于肿瘤干细胞和乳腺癌细胞表面的多巴胺受体，抑制白血病干细胞在体内的成癌作用。但尚未见该药物具有增加孕激素敏感性的报道。
目前，临床上对于有保留生殖内分泌功能需求的子宫内膜癌及癌前病变(复杂不典型增生)患者的保守治疗方式为孕激素疗法，文献[Wei J，Zhang W，Feng L，GaoW.Comparison of fertility-sparing treatments in patients with earlyendometrial cancer and atypical complex hyperplasia：A meta-analysis andsystematic review.Medicine(Baltimore).2017.96(37)：e8034.]中，曾报道了孕激素治疗早期子宫内膜癌的完全反应率仅为71％，并且即使初始对孕激素治疗敏感的患者中亦有高达33％的患者在后续治疗中出现了耐药现象。探讨孕激素的增敏机制，改善孕激素的耐药，是早、晚期子宫内膜癌临床治疗迫切需要解决的难题。
发明内容
本发明目的在于提供甲硫达嗪在甲硫达嗪在改善子宫内膜癌孕激素耐药中的应用。本发明发现，甲硫达嗪单独使用可抑制子宫内膜癌细胞的增殖和活力，甲流达嗪与孕激素联合应用还可促进孕激素不敏感的子宫内膜癌细胞的凋亡。
本发明目的是通过以下技术方案实现：
第一方面，本发明涉及甲硫达嗪在制备改善子宫内膜癌孕激素耐药的药物中的用途，所述甲硫达嗪的结构式如下：
优选的，所述甲硫达嗪单独使用，抑制子宫内膜癌细胞的增殖和活力。
优选的，所述甲硫达嗪配合孕激素使用。
更优选的，所述孕激素为醋酸甲羟孕酮。
进一步优选的，所述甲硫达嗪促进醋酸甲羟孕酮对耐孕激素子宫内膜癌细胞的杀伤作用。
第二方面，本发明还涉及一种包含甲硫达嗪的改善子宫内膜癌孕激素耐药的复方药物，是以甲硫达嗪、孕激素为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的药物。
更优选地，所述孕激素为醋酸甲羟孕酮。
与现有技术相比，本发明具有如下有益效果：
本发明发现甲硫达嗪可抑制孕激素敏感/不敏感子宫内膜癌细胞的增殖与活力，对子宫内膜癌细胞的凋亡无影响；甲硫达嗪与孕激素(MPA)联合应用可进一步促进后者对孕激素敏感/不敏感子宫内膜癌细胞的抑增殖与促凋亡作用。因此，甲硫达嗪可作为改善子宫内膜癌孕激素耐药的药物。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其它特征、目的和优点将会变得更明显：
图1为本发明的甲硫达嗪的结构图；
图2为醋酸甲羟孕酮抑制/不抑制孕激素敏感/不敏感的子宫内膜癌细胞增殖实验中CCK-8试剂染色后的定量示意图；
图3为甲硫达嗪与醋酸甲羟孕酮联合应用抑制孕激素敏感子宫内膜癌细胞增殖实验中CCK-8试剂染色后的定量示意图；
图4为甲硫达嗪与醋酸甲羟孕酮联合应用抑制孕激素不敏感子宫内膜癌细胞增殖实验中CCK-8试剂染色后的定量示意图；
图5为甲硫达嗪与醋酸甲羟孕酮联合应用抑制孕激素敏感子宫内膜癌细胞凋亡实验中流式细胞学示意图与定量示意图；
图6为甲硫达嗪与醋酸甲羟孕酮联合应用抑制孕激素不敏感子宫内膜癌细胞凋亡实验中流式细胞学示意图与定量示意图。
具体实施方式
下面结合实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干调整和改进。这些都属于本发明的保护范围。
实施例1、甲硫达嗪联合醋酸甲羟孕酮抑制子宫内膜癌细胞的增殖与活力的实验
材料如下：
细胞：子宫内膜癌细胞株Ishikawa、KLE；药物：甲硫达嗪，醋酸甲羟孕酮(Medroxyprogesterone Acetate，MPA)
方法：取对数生长期细胞密度为8×103个细胞/孔接种于96孔板培养，24h后加入不同浓度MPA(0、1、10、20、30、40、50μmol/L)，每种浓度梯度设6个平行复孔，然后置于37℃、5％CO2培养箱培养24h，进行实验。
取生长对数期细胞，按实验分组用药，每组设6个平行复孔，分别培养1、2、3、4d，进行实验。计算不同时间点细胞生长的抑制率，选定后续实验的药物作用时间。在96孔板中配置100μl的1×104细胞/孔细胞悬液，将培养板在培养箱预培养24h。药物处理分组为对照组1/1000 DMSO、MPA组10μM MPA、THIO组10uM甲硫达嗪(结构式如图1)、联合用药组10uM MPA+10uM甲硫达嗪。每种药物浓度设6个复孔，并设不加细胞液的调零孔和只加细胞液、不加肽液的空白对照孔。每孔加入10μl CCK-8检测试剂，将培养板在培养箱内孵育4h，吸去原培养液，震荡10min，用酶标仪测450nm处吸光度值(A).计算细胞存活率％＝(实验组A值-空自组A值)/(对照组A值-空白组A值)×100％。绘制生长曲线。实验重复3次。
实验结果如图2、3、4所示，由附图可知：MPA可浓度依赖性的降低子宫内膜癌细胞的生存率，当MPA作用浓度大于10μmol/L时，KLE、Ishikawa二组细胞的生存率存在组间差异，且差异有统计学意义，即KLE细胞对MPA处理不敏感。甲硫达嗪可显著抑制人子宫内膜癌细胞细胞的增殖与生长。甲硫哒嗪联合MPA可抑制Ishikawa和KLE细胞的生长力，且呈时间依赖性，对孕激素不敏感的KLE细胞作用尤为显著。
实施例2、甲硫达嗪联合醋酸甲羟孕酮抑制子宫内膜癌细胞凋亡的实验
材料如下：
方法：取对数生长期的细胞常规消化，细胞接种24h后换以无血清培养液培养18h，加入实验药物72h后(药物处理分组同实例1)，常规无EDTA胰酶消化，使用冷的PBS缓冲液冲洗细胞两次，再用1×Binding Buffer缓冲液制成1×106单细胞悬液，离心弃上清液，再经预冷的磷酸盐缓冲液(PBS)洗2次，Falcon试管中加入100μl细胞悬液，分别加入AnnexinV-FITC和核算染料(PI)各5μl染料，轻轻混匀，室温避光处放置15min。各试管中分别加入1×Binding Buffer缓冲液400μl。1h内上流式分析仪检测。实验重复3次。
实验结果如图5、6所示，由附图可得知：MPA组与对照组相比，Ishikawa细胞凋亡率具有显著差异(P＜0.01)，而KLE细胞凋亡率组间无统计学差异。联合用药组与空白对照/MPA组相比，细胞凋亡率均显著升高，Ishikawa(P＜0.001)和KLE(P＜0.01)。说明MPA对Ishikawa细胞有促凋亡作用，但对KLE细胞作用不明显；甲硫哒嗪联合孕激素可显著升高子宫内膜癌细胞Ishikawa及KLE细胞凋亡率。
经实验证实：本发明的甲硫达嗪可抑制孕激素敏感/不敏感子宫内膜癌细胞的增殖与活力，对子宫内膜癌细胞的凋亡无影响。MPA可抑制子宫内膜癌细胞的增殖与凋亡，甲硫达嗪与MPA联合应用可进一步促进后者对孕激素敏感/不敏感子宫内膜癌细胞的抑增殖与促凋亡作用。因此，甲硫达嗪可用于改善耐孕激素子宫内膜癌的治疗效果。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。

Claims (7)

1.甲硫达嗪在制备改善子宫内膜癌孕激素耐药的药物中的用途，所述甲硫达嗪的结构式如下：
2.如权利要求1所述的用途，其特征在于，所述甲硫达嗪单独使用，抑制子宫内膜癌细胞的增殖和活力。
3.如权利要求1所述的用途，其特征在于，所述甲硫达嗪与孕激素联用。
4.如权利要求3所述的用途，其特征在于，所述孕激素为醋酸甲羟孕酮。
5.如权利要求4所述的用途，其特征在于，所述甲硫达嗪促进醋酸甲羟孕酮对耐孕激素子宫内膜癌细胞的杀伤作用。
6.一种包含甲硫达嗪的改善子宫内膜癌孕激素耐药的复方药物，是以甲硫达嗪、孕激素为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的药物。
7.如权利要求6所述的复方药物，其特征在于，所述孕激素为醋酸甲羟孕酮。
CN201811317554.9A 2018-11-05 2018-11-05 甲硫达嗪在改善子宫内膜癌孕激素耐药中的应用 Pending CN109528728A (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115656392A (zh) * 2022-12-14 2023-01-31 山东大学齐鲁医院 尿液代谢物在制备鉴别子宫内膜癌保留生育功能治疗孕激素耐药患者的产品中的应用
WO2023035201A1 (zh) * 2021-09-09 2023-03-16 中国福利会国际和平妇幼保健院 五氟利多联合醋酸甲羟孕酮在制备治疗子宫内膜癌的药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103800299A (zh) * 2014-02-25 2014-05-21 刘艳青 一种醋酸甲羟孕酮片及其制备工艺

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103800299A (zh) * 2014-02-25 2014-05-21 刘艳青 一种醋酸甲羟孕酮片及其制备工艺

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
QIONG MENG等: "The important application of thioridazine in the endometrial cancer", 《AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH》 *
WANG J等: "Mechanism of Survivin-Autophagy Pathway Regulates Thioridazine Sensitizing Progestin-Resistance Endometrial Cancer", 《JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY》 *
孟琼等: "甲硫哒嗪联合孕激素抑制子宫内膜癌细胞增殖的作用机制", 《中华医学杂志》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023035201A1 (zh) * 2021-09-09 2023-03-16 中国福利会国际和平妇幼保健院 五氟利多联合醋酸甲羟孕酮在制备治疗子宫内膜癌的药物中的应用
CN115656392A (zh) * 2022-12-14 2023-01-31 山东大学齐鲁医院 尿液代谢物在制备鉴别子宫内膜癌保留生育功能治疗孕激素耐药患者的产品中的应用
CN115656392B (zh) * 2022-12-14 2023-04-07 山东大学齐鲁医院 尿液代谢物在制备鉴别子宫内膜癌保留生育功能治疗孕激素耐药患者的产品中的应用

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