CN104739822A - 淫羊藿素在制备ampk激动剂中的应用 - Google Patents

淫羊藿素在制备ampk激动剂中的应用 Download PDF

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Publication number
CN104739822A
CN104739822A CN201410077627.7A CN201410077627A CN104739822A CN 104739822 A CN104739822 A CN 104739822A CN 201410077627 A CN201410077627 A CN 201410077627A CN 104739822 A CN104739822 A CN 104739822A
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Prior art keywords
ampk
icaritin
chromen
trihydroxy
enyl
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徐金华
吴金峰
王上上
董竞成
秦海红
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Huashan Hospital of Fudan University
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Huashan Hospital of Fudan University
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Abstract

本发明属药物制备领域。涉及淫羊藿素的医药新用途，具体涉及淫羊藿素在制备AMPK激动剂中的应用。本发明进行了体外细胞实验，结果显示，淫羊藿素可显著增加黑色素瘤细胞A375磷酸化AMPK的表达；并可浓度依赖性地降低A375的细胞活性；采用RNA干扰技术沉默AMPK基因后，淫羊藿素抑制黑色素瘤增殖的作用被逆转；实验结果表明，所述的淫羊藿素可制备AMPK激动剂，诱导AMPK磷酸化，进而抑制黑色素瘤A375的增殖。本发明的淫羊藿素可作为药物有效成分，加以药物学上可接受的载体，制备激活AMPK的药物组合物，尤其用于制备抗黑色素瘤药物。

Description

淫羊藿素在制备AMPK激动剂中的应用
技术领域
本发明属药物制备领域，涉及淫羊藿素的医药新用途，具体涉及淫羊藿素在制备AMPK激动剂中的应用。
背景技术
据文献报道，单磷酸腺苷活化蛋白激酶(AMPK)是一个调控能量稳态的重要激酶,也是一个参与许多细胞信号传导通路的关键蛋白。研究显示，AMPK不仅在代谢障碍而且在心血管疾病及生殖障碍等许多病理状态中都具有重要的调节作用。此外,AMPK在人类恶性肿瘤中也扮演着重要的角色。AMPK已成为医药技术领域广受关注的药物靶点。目前已知AMPK的激动剂有AICAR、A769662和metformin（二甲双胍）等；新近的研究发现天然药物黄连素也被认为是一种AMPK激动剂。从天然药物中寻找新型AMPK激动剂是目前研究的热点。已知淫羊藿素属黄酮醇类化合物，其少量存在于淫羊藿药材中，其化学结构式如下：
目前有关淫羊藿素的药理活性研究报道公开了淫羊藿素具有抗炎症、抗抑郁和抗骨质疏松等药理作用，关于淫羊藿素作为AMPK激动剂的用途尚未见报道。
发明内容
本发明的目的在于提供淫羊藿素的新的药用用途，具体涉及淫羊藿素在制备AMPK激动剂中的应用。所述的淫羊藿素可显著增加黑色素瘤细胞A375磷酸化AMPK的表达；抑制黑色素瘤细胞的增殖。
本发明所采用的淫羊藿素（可市购）属黄酮醇类化合物，少量存在于淫羊藿药材中，其化学结构式如下：
本发明将上述淫羊藿素进行了体外细胞实验，结果显示，淫羊藿素可显著增加黑色素瘤细胞A375磷酸化AMPK的表达；并可浓度依赖性地降低A375的细胞活性；采用RNA干扰技术沉默AMPK基因后，淫羊藿素抑制黑色素瘤增殖的作用被逆转；实验结果表明，所述的淫羊藿素可制备AMPK激动剂，诱导AMPK磷酸化，进而抑制黑色素瘤A375的增殖。
所述的淫羊藿素可以作为药物有效成分，加以药物学上可接受的载体，制备激活AMPK的药物组合物，尤其用于制备抗黑色素瘤药物。
附图说明
图1显示了淫羊藿素增加磷酸化AMPK蛋白表达（western blot法）。
图2显示了淫羊藿素抑制黑色素瘤A375的细胞活性（MTT法）。
图3显示了淫羊藿素IT抑制黑色素瘤A375的细胞增殖（细胞自动计数仪）。
图4显示了淫羊藿素对AMPK的活化作用被逆转，其中，AMPK RNA干扰48h后AMPK和P-AMPK蛋白表达明显下降
图5显示了AMPK RNA干扰48h后淫羊藿素对抑制黑色素瘤细胞活性的作用被部分逆转。
具体实施方式
实施例1
采用western blot的方法，观察淫羊藿素对黑色素瘤细胞A375磷酸化AMPK的表达影响，结果显示，淫羊藿素10μM作用2h可显著增加黑色素瘤细胞A375磷酸化AMPK的表达（如图1所示）。
实施例2
采用不同浓度的淫羊藿素（0，1,10,20,40,80μM）分别作用于人黑色素瘤细胞A375，48h后MTT法观察细胞活性的变化，结果显示，淫羊藿素可浓度依赖性地降低A375的细胞活性，其IC50值为3.96μM（如图2所示）；
采用罗氏全自动细胞计数仪计数，结果显示，2×105A375细胞培养48h后，对照组细胞数为1.55×106，淫羊藿素1μM组为1.25×106，而淫羊藿素10μM组为0.53×106，提示淫羊藿素可明显抑制黑色素瘤细胞的增殖，与MTT的结果相一致（如图3所示）。
实施例3
AMPK基因沉默后，淫羊藿素抑制黑色素瘤增殖的作用被逆转，
本实施例进行了RNA干扰实验，结果显示，AMPK siRNA转染48h后，AMPK和P-AMPK蛋白表达明显下降（如图4所示），淫羊藿素10μM对AMPK的活化作用被逆转，与此同时，淫羊藿素10μM抑制黑色素瘤增殖的作用也被部分逆转（如图5所示）。
本发明的实验证实所述的淫羊藿素可制备AMPK激动剂，能增加磷酸化AMPK蛋白表达，抑制黑色素瘤细胞A375的增殖；所述的淫羊藿素与药物学上可接受的载体可进一步制备激活AMPK的药物组合物，尤其是制备抗黑色素瘤的药物。

Claims (3)

1.式（1）的淫羊藿素在制备AMPK激动剂中的应用,
2.式（1）的淫羊藿素在制备抗黑色素瘤药物中的应用。
3.一种激活AMPK的药物组合物，其特征在于含有式（1）的淫羊藿素及药物学上可接受的载体。
CN201410077627.7A 2013-12-28 2014-03-05 淫羊藿素在制备ampk激动剂中的应用 Pending CN104739822A (zh)

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CN101439042A (zh) * 2007-11-23 2009-05-27 华北制药集团新药研究开发有限责任公司 一类异戊烯基黄酮苷化合物的抗肿瘤用途
CN101528038A (zh) * 2006-10-25 2009-09-09 盛诺基医药科技有限公司 用于治疗与雌激素受体相关的疾病的化合物和方法
CN102068448A (zh) * 2009-11-19 2011-05-25 复旦大学附属华山医院 淫羊藿次苷ⅱ在制备抗黑色素瘤药物中的用途
CN102106864A (zh) * 2009-12-23 2011-06-29 复旦大学附属华山医院 淫羊藿苷在制备拮抗髓系衍生抑制性细胞药物中的应用

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CN101528038A (zh) * 2006-10-25 2009-09-09 盛诺基医药科技有限公司 用于治疗与雌激素受体相关的疾病的化合物和方法
CN101439042A (zh) * 2007-11-23 2009-05-27 华北制药集团新药研究开发有限责任公司 一类异戊烯基黄酮苷化合物的抗肿瘤用途
CN102068448A (zh) * 2009-11-19 2011-05-25 复旦大学附属华山医院 淫羊藿次苷ⅱ在制备抗黑色素瘤药物中的用途
CN102106864A (zh) * 2009-12-23 2011-06-29 复旦大学附属华山医院 淫羊藿苷在制备拮抗髓系衍生抑制性细胞药物中的应用

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Application publication date: 20150701