CN107714686A - 磷酸二酯酶4抑制剂ZL‑n‑91在制备治疗前列腺癌增生和转移药物中的应用 - Google Patents
磷酸二酯酶4抑制剂ZL‑n‑91在制备治疗前列腺癌增生和转移药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种新型磷酸二酯酶4(PDE4)抑制剂ZL‑n‑91在制备治疗抗前列腺癌增殖和转移药物中的应用。利用在小鼠的动物实验和细胞学实验表明本发明所述磷酸二酯酶4抑制剂ZL‑n‑91可以显著抑制前列腺癌细胞的增殖和转移，预示该磷酸二酯酶4抑制剂ZL‑n‑91有望成为抗前列腺癌增殖和转移研究的重要靶点，为制备抗前列腺癌增殖和转移药物提供了基础，具有良好的开发应用前景。
Description
技术领域
本发明涉及一种磷酸二酯酶4抑制剂的应用，尤其涉及一种磷酸二酯酶4抑制剂ZL-n-91的应用，属于肿瘤生物学领域。
背景技术
前列腺癌是欧美国家男性最常见的恶性肿瘤，其发病率在美国位于男性恶性肿瘤第一位，其死亡率仅次于肺癌居第二位。近年来，在我国其发病率也呈现逐年上升的趋势，且前列腺癌的组织学恶性程度高于美国患者。据国内上海市区对泌尿系恶性肿瘤患者的相对生存率调查发现，在中国80.0％～90.0％的患者在就诊时已经是晚期前列腺癌，5年生存率不到30％。由于我国人口基数大，前列腺癌患病人数激增，必须重视前列腺癌的预防和治疗。前列腺癌的传统治疗方法包括手术、内分泌治疗和放、化疗，治疗效果并不十分理想。手术治疗后复发率比较高。对于复发的前列腺癌，往往需要采取雄激素剥夺的内分泌治疗。内分泌治疗持续治疗2～5年后，前列腺癌一般会发展为雄激素非依赖性。对于雄激素非依赖性前列腺癌患者，目前的治疗方法包括化疗、放疗、核素内照射以及双磷酸盐治疗等，疗效均不满意。前列腺癌的治疗陷入窘境，迫切需要新的更有效的治疗方案。因此科学家和临床专家们一直在积极探索更为安全有效的治疗方案
磷酸二酯酶(简称PDEs)具有水解细胞内第二信使cAMP或cGMP的功能，从而影响这些第二信使所介导的信号通路，调节细胞功能。PDEs共分为11个亚型，其中磷酸二酯酶4(PDE4)特异性水解cAMP。PDE4主要分布于各种炎性细胞内，包括肥大细胞、巨噬细胞淋巴细胞、上皮细胞等，参与了促进单核细胞与巨噬细胞活化、中性粒细胞浸润、血管平滑肌的增殖、血管扩张以及心肌收缩等相关生理病理过程，对中枢神经系统功能、心血管功能、炎症/免疫系统、细胞黏附等都有影响。研究显示，PDE4抑制剂(PDE4i)具有抗炎、抗过敏、抗血小板活化作用。其作用机制主要涉及：1)抑制多种炎症介质/细胞因子的释放，能够抑制IL-4、IL-5基因的表达；2)抑制白细胞的激活(如呼吸爆发)，抑制白细胞游走；3)抑制细胞粘附因子(CAM)的表达或上调；4)诱导产生具有抑制活性的细胞子，如IL-6；5)诱导细胞凋亡；6)刺激内源性激素和儿茶酚胺类物质的释放。
虽然已经开发或正在开发的PDE4抑制剂针对的疾病主要是慢性阻塞性肺疾病(COPD)、哮喘、炎症性肠疾病、关节炎等。但是，很多研究表明PDE4抑制剂对于恶性肿瘤也有显著的抑制作用。Patricia Goldhoff给裸鼠异种移植入人脑星形胶质母细胞瘤细胞U87后，使用PDE4抑制剂可以延长小鼠生存期。2006年Motoshi Narita发现PDE4i可以抑制人黑色素瘤细胞的生长，Petros X.E.Mouratidis发现在胰腺癌细胞中加入PDE4抑制剂CC-8075和CC-8062后，可以使其细胞增殖降低和细胞凋亡增加。
现有的PDE4抑制剂主要有咯利普兰(Rolipram)、西洛司特(Cilomilast)、罗氟司特(Roflumilast)等。由于Rolipram和Cilomilast引发头晕、头痛和恶心、呕吐等胃肠道不良反应，影响了药物在临床中推广应用。导致胃肠道不良反应的可能原因之一是PDE4抑制剂特异性差，从而中度选择性地抑制了整个PDE家族。如Cilomilast对PDE4的Ki＝92nM，仅是PDE1、2、3、5的Ki的500到1000倍。因此使用较高剂量Cilomilast会与其他PDE家族成员发生作用从而产生副作用。事实上，大多数PDE4抑制剂，在高剂量时产生呕吐的副作用是普遍现象。Roflumilast虽然已经通过美国FDA批准上市用于治疗COPD，降低肺部的炎症、抵抗氧化应激、有效的缓解肺部的纤维化、增强粘膜的清除能力以及气道的重塑等等。但是也有不良反应，主要表现为腹泻、体重下降、恶心、心房纤颤及精神方面疾病的加重(如失眠、焦虑、抑郁)等。
发明内容
本发明所要解决的技术问题是提供一种磷酸二酯酶4抑制剂ZL-n-91在制备抗前列腺癌增殖药物中的应用。
为解决上述技术问题，采用的技术方案如下：
磷酸二酯酶4抑制剂ZL-n-91在制备抗前列腺癌增殖药物中的应用在本发明的保护范围之内。
本发明利用体外肿瘤细胞培养及裸鼠皮下种植瘤模型，研究ZL-n-91的病理生理学作用。实验证实：该抑制剂能够显著抑制人前列腺癌PC-3细胞的增殖以及移植瘤的生长，为制备抗前列腺癌增殖药物的研究奠定了基础。
磷酸二酯酶4抑制剂ZL-n-91在制备抗前列腺癌转移药物中的应用也在本发明的保护范围之内。
本发明利用人前列腺癌细胞PC-3，研究了ZL-n-91的生物学作用。实验结果显示：该抑制剂能够显著抑制前列腺癌细胞的迁移，为制备抗前列腺癌转移药物的研究奠定了基础。
磷酸二酯酶4抑制剂ZL-n-91在制备抗前列腺癌增殖与转移药物中的应用也在本发明的保护范围之内。
以上应用的给药方式优选为口服、注射或吸雾给药。
本发明所述的磷酸二酯酶4抑制剂ZL-n-91，其结构式如下：
本发明所述的磷酸二酯酶4抑制剂ZL-n-91可直接购买或者自行合成，例如可以参考文献[Ruihong Ma,Bin-yan Yang,Chang-you Wu.A selective phosphodiesterase 4(PDE4)inhibitor Zl-n-91 suppresses IL-17 production by human memory Th17cells.International Immunopharmacology,2008,8(10):1408-1417.]自行合成制备。
为了更好的证明本发明所述化合物的作用效果，下面实施例结合小鼠的体内移植瘤生长抑制实验与体外细胞实验，来进一步阐明本发明所述磷酸二酯酶抑制剂ZL-n-91在抗前列腺癌增殖与转移中所具有的作用。
有益效果：本发明所述的选择性PDE4抑制剂ZL-n-91，可以显著抑制肿瘤细胞的增殖和迁移，预示该磷酸二酯酶4抑制剂ZL-n-91有望成为抗前列腺癌增殖和转移研究的重要靶点，为制备抗前列腺癌增殖药物提供了基础，具有良好的开发应用前景。ZL-n-91对PDE4D的抑制剂强度是其他PDE家族成员的5000倍以上。相比其他PDE4抑制剂，该化合物对PDE4D具有更高的选择性，特异性强，产生的副作用小，能有效减弱甚至避免呕吐等不良反应。
附图说明
图1左图和右图分别是人前列腺癌细胞PC-3给予不同剂量ZL-n-91后24小时及48小时细胞增殖结果图。
图2是人前列腺癌细胞PC-3皮下种植瘤裸鼠给予不同剂量ZL-n-91后，各组小鼠体重变化图。
图3是人前列腺癌细胞PC-3皮下种植瘤裸鼠给予不同剂量ZL-n-91后，肿瘤体积变化图和肿瘤重量图。
图4是人前列腺癌细胞PC-3皮下种植瘤裸鼠给予不同剂量ZL-n-91后，肿瘤大小图片。
图5是人前列腺癌细胞PC-3皮下种植瘤裸鼠给予不同剂量ZL-n-91后，肿瘤组织中Ki67表达，左图是免疫组化结果，右图为其量化结果。
图6是人前列腺癌细胞PC-3给予不同剂量ZL-n-91后24小时细胞迁移结果图。
具体实施方式
根据下述实施例，可以更好地理解本发明。然而，本领域的技术人员容易理解，实施例所描述的内容仅用于说明本发明，而不应当也不会限制权利要求书中所详细描述的本发明。
实施例1：CCK8法检测ZL-n-91对前列腺癌细胞增殖的影响。
1)取对数生长期的PC-3细胞，制备单细胞悬液。按每孔100ul细胞悬液(含1×104个细胞)接种于96孔板中，共分为5组，空白对照组，10uM，50uM，100uM，200uM组，每组6个复孔，将细胞预培养24小时(在37℃，5％CO2的条件下)；
2)更换新鲜培养基，各组分别加入不同浓度的ZL-n-91，将细胞继续分别培养24小时和48小时(在37℃，5％CO2的条件下)；
3)向每孔加入100ul含10％的CCK-8溶液，避免产生气泡；
4)将细胞继续孵育1-2小时，分别在30min，60min，90min，将培养板取出，用酶标仪测定在450nm处的吸光度。
结果如图1所示：随着ZL-n-91浓度的升高，人前列腺癌细胞PC-3的增殖能力显著性降低。
实施例2：PC-3皮下种植瘤裸鼠的治疗。
1)取对数生长期的PC-3细胞，用无血清F-12K培养基制备单细胞悬液，按每管120ul细胞悬液(含2×106个细胞)分装于1.5mlEP管中；
2)用1ml无菌注射器吸取制备好的细胞悬液0.1ml接种于裸鼠皮下；
3)接种3天后给予小鼠药物治疗。
4)将裸鼠分为两组：溶剂对照组和给药组(10mg/kg)，每天灌胃药物治疗，并每周两次测量裸鼠皮下肿瘤体积和小鼠体重；
5)当小鼠肿瘤体积达到1500mm3时，取出小鼠肿瘤，比较肿瘤大小，并记录肿瘤重量。
结果如图2表明，给与药物治疗对小鼠体重无影响，如图3、4所示，给予药物治疗后，肿瘤体积和重量量约为对照组的1/2，说明ZL-n-91对于PC-3皮下种植瘤的生长有显著抑制作用。
实验例3：ZL-n-91抑制移植肿瘤组织中Ki-67的表达。
取以上所述肿瘤组织，用4％福尔马林固定过夜，经石蜡包埋切片，进行肿瘤增殖抗原Ki67染色。
结果如图5所示，给药组肿瘤组织的Ki67染色阳性率与空白组相比有显著降低，说明给药组肿瘤细胞的增殖减少。
实施例4：ZL-n-91对人前列腺癌细胞PC-3转移能力的影响。
1)取对数生长期的细胞，用无血清DMEM培养基制成悬液。按每孔100ul细胞悬液(含5×104个细胞)接种于transwell小室中。分为3组：空白对照组，10uM，50uM组，每组设3个复孔，并给予不同浓度的药物处理；
2)将10％FBS的完全DMEM培养基加入12孔板下室，然后放入小室；
3)24小时后，取出小室，置于冰甲醇中固定30min，室温下自然晾干；
4)在12孔板分别加入600ul含0.1％结晶紫溶液浸泡小室下表面15min，将细胞染成紫色；
5)加入PBS，5min后将PBS吸出，用干净棉签轻轻擦去小室内的细胞。PBS洗3遍。室温下自然晾干；
6)在12孔板内加入10％乙酸溶液300ul，将小室下表面浸泡10min，溶解细胞中的结晶紫颗粒；
7)各孔取100ul溶液置于96孔酶联板中，用酶标仪测定在570nm处的吸光度。
结果如图6显示：当药物浓度为50uM时，ZL-n-91对人前列腺癌PC-3细胞的转移有抑制作用。
以上研究结果表明，本发明所采用的磷酸二酯酶4抑制剂ZL-n-91能抑制前列腺癌细胞增殖和转移，具有良好的抗肿瘤效果。
Claims (4)
1.磷酸二酯酶4抑制剂ZL-n-91在制备抑制前列腺癌增生药物中的应用。
2.磷酸二酯酶4抑制剂ZL-n-91在制备抵抗前列腺癌转移药物中的应用。
3.磷酸二酯酶4抑制剂ZL-n-91在制备治疗前列腺癌增生与转移药物中的应用。
4.根据权利要求1～3所述的应用，其特征在于，可以口服、注射和雾化形式给药。
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| AU2017309221A AU2017309221A1 (en) | 2016-08-10 | 2017-08-08 | Application of phosphodiesterase 4 inhibitor ZL-n-91 in preparation of medicament for treating prostate cancer proliferation and metastasis |
| EP17838690.0A EP3498274B1 (en) | 2016-08-10 | 2017-08-08 | Application of phosphodiesterase 4 inhibitor zl-n-91 in preparation of medicament for treating prostate cancer proliferation and metastasis |
| PCT/CN2017/096399 WO2018028560A1 (zh) | 2016-08-10 | 2017-08-08 | 磷酸二酯酶4抑制剂ZL-n-91在制备治疗前列腺癌增生和转移药物中的应用 |
| JP2019507245A JP6980005B2 (ja) | 2016-08-10 | 2017-08-08 | 前立腺がんの増殖および転移を処置するための医薬品の調製におけるホスホジエステラーゼ４阻害剤ＺＬ−ｎ−９１の適用 |
| US16/322,112 US20190160036A1 (en) | 2016-08-10 | 2017-08-08 | Application of phosphodiesterase 4 inhibitor zl-n-91 in preparation of medicament for treating prostate cancer proliferation and metastasis |
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| WO2021208295A1 (zh) * | 2020-04-16 | 2021-10-21 | 广州华真医药科技有限公司 | Pde4抑制剂在制备治疗白血病的药物中的应用 |
| CN113876761A (zh) * | 2020-07-01 | 2022-01-04 | 广州华真医药科技有限公司 | 磷酸二酯酶4抑制剂ZL-n-91在制备抗骨肉瘤药物中的应用 |
| CN114917217A (zh) * | 2022-05-20 | 2022-08-19 | 广东工业大学 | 磷酸二酯酶4抑制剂ZL-n-91在制备治疗三阴性乳腺癌的药物中的应用 |
| CN115381954A (zh) * | 2021-05-21 | 2022-11-25 | 广州华真医药科技有限公司 | 一种用于治疗骨肉瘤的联合用药物 |
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| WO2021208295A1 (zh) * | 2020-04-16 | 2021-10-21 | 广州华真医药科技有限公司 | Pde4抑制剂在制备治疗白血病的药物中的应用 |
| CN113521054A (zh) * | 2020-04-16 | 2021-10-22 | 广州华真医药科技有限公司 | Pde4抑制剂在制备抑制胶质瘤增殖的药物中的应用 |
| CN113521053A (zh) * | 2020-04-16 | 2021-10-22 | 广州华真医药科技有限公司 | Pde4抑制剂在制备治疗白血病的药物中的应用 |
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| WO2022000708A1 (zh) * | 2020-07-01 | 2022-01-06 | 广州华真医药科技有限公司 | 磷酸二酯酶4抑制剂ZL-n-91在制备抗骨肉瘤药物中的应用 |
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| CN115381954A (zh) * | 2021-05-21 | 2022-11-25 | 广州华真医药科技有限公司 | 一种用于治疗骨肉瘤的联合用药物 |
| CN115381954B (zh) * | 2021-05-21 | 2023-12-05 | 深圳市翰慧医药科技有限公司 | 一种用于治疗骨肉瘤的联合用药物 |
| CN114917217A (zh) * | 2022-05-20 | 2022-08-19 | 广东工业大学 | 磷酸二酯酶4抑制剂ZL-n-91在制备治疗三阴性乳腺癌的药物中的应用 |
| CN114917217B (zh) * | 2022-05-20 | 2023-09-12 | 广东工业大学 | 磷酸二酯酶4抑制剂ZL-n-91在制备治疗三阴性乳腺癌的药物中的应用 |
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| US20190160036A1 (en) | 2019-05-30 |
| AU2017309221A1 (en) | 2019-02-14 |
| CN107714686B (zh) | 2020-01-14 |
| JP2019524812A (ja) | 2019-09-05 |
| EP3498274B1 (en) | 2023-12-13 |
| WO2018028560A1 (zh) | 2018-02-15 |
| EP3498274C0 (en) | 2023-12-13 |
| EP3498274A4 (en) | 2020-08-19 |
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| EP3498274A1 (en) | 2019-06-19 |
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