CN101822663B - 异硫氰酸酯在制备防治耐药肿瘤药物的用途 - Google Patents
异硫氰酸酯在制备防治耐药肿瘤药物的用途 Download PDFInfo
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Abstract
本发明公开了异硫氰酸酯在制备防治耐药肿瘤药物的用途。本发明运用细胞生物学和分子生物学方法，证明异硫氰酸酯能有效抑制耐药肿瘤细胞生长，诱导凋亡，调控肿瘤耐药相关基因，引起耐药肿瘤细胞周期停滞，造成肿瘤细胞氧化损伤。因此，可以将异硫氰酸酯作为有效成分制备防治耐药肿瘤药物及防治耐药肿瘤食品、保健品及化妆品。
Description
技术领域
本发明属于医药应用领域，涉及异硫氰酸酯在制备防治耐药肿瘤药物的用途。
背景技术
我国癌症的发病率与死亡率呈快速上升的趋势。癌症给患者本人及家庭造成极大痛苦，也占用了大量的社会资源和财富，癌症已经成为人类面临的日益严重的公共卫生问题。各国政府都投入了大量的人力物力，以期在癌症研究领域有所突破。
目前癌症的主要治疗方法是外科手术治疗、放疗、化疗和生物治疗等。外科手术治疗是最有效的治疗手段。然而绝大多数患者就诊时就已经是中晚期，或者是晚期，错过了手术治疗的机会。放射治疗为一种局部治疗，其疗效是有限的，同时亦有剂量限制性、毒性问题。化疗可应用于几乎全部癌症患者，因此抗肿瘤药物治疗成为中晚期癌症患者的主要治疗手段。然而绝大多数化疗病人最终都死于肿瘤耐药和肿瘤转移。影响化疗效果的一个重要问题是肿瘤细胞产生了对细胞毒药物的耐药性。肿瘤耐药性的产生成为治愈癌症的重大障碍[1，2]。因此克服肿瘤耐药成为肿瘤治疗中急待攻克的难题。
对于肿瘤的耐药性，国内外已开展了大量研究。根据肿瘤细胞的耐药特点，耐药可分为原发性耐药(primary drug resistance)和获得性耐药(acquired drug resistance)两大类。原发性耐药在化疗前就存在于肿瘤细胞中，与药物的使用无关；获得性耐药是由于化疗药物作用于肿瘤细胞后，对使用过的相同药物或/和其它化学结构和作用机制完全不同的药物产生的耐药。原发性耐药的肿瘤，一开始对抗肿瘤药物就具有抗药性，包括消化系统、呼吸系统、泌尿系统以及中枢神经系统肿瘤，约占61％；获得性耐药的肿瘤，包括皮肤癌、乳腺癌、生殖器癌、内分泌肿瘤、白血病和淋巴瘤，约占33％。许多天然来源的抗肿瘤药物，如生物碱类抗癌药物(秋水仙碱、长春碱、三尖杉酯碱和紫杉醇等)，蒽环类抗癌抗生素(阿霉素和柔红霉素)，表鬼臼毒素类(Vp-16和VM-26)，及合成药(米托蒽醌和胺苯丫啶)都极易引发耐药性。
鉴于目前抗肿瘤药物对耐药肿瘤疗效不理想，且具毒副作用的特点，开发新型抗耐药肿瘤药物成为攻克癌症的难点。其中研究和开发天然抗耐药肿瘤药物是目前抗肿瘤药物研发中的前沿和热点课题。
异硫氰酸酯(isothiocyanate)是一种有机小分子化合物，普遍存在于蔬菜中[3]。它是天然存在于十字花科蔬菜(如辣根、花椰菜、卷心菜等)中的硫代葡萄糖苷的降解产物。最早引起人们关注的是它具有防癌作用，能抑制多种肿瘤的生成，如肺、胃、结肠、肝、食管、膀胱、乳腺等部位[4-7]。其作用机制是抑制致癌物的活化，如降低细胞色素P450的活性[8]；同时促进致癌物的排出，如增高谷胱甘肽转移酶的活性[9]。异硫氰酸酯防治耐药肿瘤的作用目前还未见报道。
发明内容
本发明的目的是提供异硫氰酸酯在制备防治耐药肿瘤药物的用途。
本发明的技术方案概述如下：
异硫氰酸酯在制备防治耐药肿瘤药物的用途。
所述异硫氰酸酯为异硫氰酸苄酯或异硫氰酸苯乙酯，所述异硫氰酸苄酯的分子式为C6H5CH2NCS；结构式为：
所述异硫氰酸苯乙酯的分子式为C6H5CH2CH2NCS；结构式为：
所述耐药肿瘤为耐药肺癌，耐药肝癌，耐药食道癌，耐药胃癌，耐药结肠癌，耐药胰腺癌，耐药乳腺癌，耐药宫颈癌，耐药卵巢癌，耐药前列腺癌，耐药阴茎癌，耐药黑色素瘤，耐药脑瘤，耐药口腔肿瘤，耐药耳癌，耐药鼻咽癌和/或耐药舌癌。
本发明运用细胞生物学和分子生物学方法，证明异硫氰酸酯能有效抑制人肿瘤耐药细胞生长。异硫氰酸酯有效抑制耐药肿瘤细胞生长，诱导凋亡，调控肿瘤耐药相关基因，引起肿瘤细胞周期停滞，造成肿瘤细胞氧化损伤。因此，可以将异硫氰酸酯作为有效成分制备防治耐药肿瘤药物及防治耐药肿瘤食品、保健品及化妆品。
附图说明
图1为异硫氰酸苄酯抑制人肺癌顺铂敏感细胞系A549细胞生长的剂量--生长曲线。图中异硫氰酸苄酯浓度范围为1-40μM，处理时间为48小时。
图2为异硫氰酸苄酯抑制人肺癌顺铂耐药细胞系A549/DDP细胞生长的剂量--生长曲线。图中异硫氰酸苄酯浓度范围为1-40μM，处理时间为48小时。
图3为异硫氰酸苄酯抑制人肺癌吉非替尼敏感细胞系PC9细胞生长的剂量--生长曲线。图中异硫氰酸苄酯浓度范围为1-40μM，处理时间为48小时。
图4为异硫氰酸苄酯抑制人肺癌吉非替尼耐药细胞系PC9/AB2细胞生长的剂量--生长曲线。图中异硫氰酸苄酯浓度范围为1-40μM，处理时间为48小时。
图5为异硫氰酸苯乙酯抑制人肺癌顺铂敏感细胞系A549细胞生长的剂量--生长曲线。图中异硫氰酸苯乙酯浓度范围为1-40μM，处理时间为48小时。
图6为异硫氰酸苯乙酯抑制人肺癌顺铂耐药细胞系A549/DDP细胞生长的剂量--生长曲线。图中异硫氰酸苯乙酯浓度范围为1-40μM，处理时间为48小时。
图7为异硫氰酸苯乙酯抑制人肺癌吉非替尼敏感细胞系PC9细胞生长的剂量--生长曲线。图中异硫氰酸苯乙酯浓度范围为1-40μM，处理时间为48小时。
图8为异硫氰酸苯乙酯抑制人肺癌吉非替尼耐药细胞系PC9/AB2细胞生长的剂量--生长曲线。图中异硫氰酸苯乙酯浓度范围为1-40μM，处理时间为48小时。
图9为实时定量PCR法检测异硫氰酸苄酯对人肺癌顺铂耐药细胞系A549/DDP中肿瘤耐药相关基因MRP1和NQO1的mRNA表达水平的调控。异硫氰酸苄酯浓度10μM，作用时间4小时。
图10为实时定量PCR法检测异硫氰酸苄酯对人肺癌吉非替尼耐药细胞系PC9/AB2中肿瘤耐药相关基因MRP1和NQO1的mRNA表达水平的调控。异硫氰酸苄酯浓度为10μM，作用时间为4小时。
图11为流式细胞术检测异硫氰酸苄酯诱导人肺癌顺铂耐药细胞系A549/DDP细胞凋亡。异硫氰酸苄酯浓度为10μM，作用时间为24小时。细胞经propidium iodide(PI)和Annexin V--FITC双染色。图11-1：对照组；图11-2：BITC处理。
图12为流式细胞术检测异硫氰酸苄酯诱导人肺癌吉非替尼耐药细胞系PC9/AB2细胞凋亡。异硫氰酸苄酯浓度为10μM，作用时间为24小时。细胞经propidium iodide(PI)和Annexin V--FITC双染色。图12-1：对照组；图12-2：BITC处理。
图13为流式细胞术检测异硫氰酸苯乙酯诱导人肺癌顺铂耐药细胞系A549/DDP细胞凋亡。异硫氰酸苯乙酯浓度为10μM，作用时间为24小时。细胞经propidium iodide(PI)和Annexin V--FITC双染色。图13-1：对照组；图13-2：PEITC处理。
图14为流式细胞术检测异硫氰酸苯乙酯诱导人肺癌吉非替尼耐药细胞系PC9/AB2细胞凋亡。异硫氰酸苯乙酯浓度为10μM，作用时间为24小时。细胞经propidium iodide(PI)和Annexin V--FITC双染色。图14-1：对照组；图14-2：PEITC处理。
图15为异硫氰酸苄酯诱导凋亡细胞的比例。
图16为异硫氰酸苯乙酯诱导凋亡细胞的比例。
图17为流式细胞术检测人肺癌顺铂耐药细胞系A549/DDP细胞周期。细胞经propidium iodide(PI)染色。异硫氰酸苄酯浓度为10μM，作用时间为24小时。图17-1：对照组；图17-2：BITC处理。
图18为流式细胞术检测人肺癌吉非替尼耐药细胞系PC9/AB2细胞周期。细胞经propidium iodide(PI)染色。异硫氰酸苄酯浓度为10μM，作用时间为24小时。图18-1：对照组；图18-2：BITC处理。
图19为流式细胞术检测人肺癌顺铂耐药细胞系A549/DDP细胞内活性氧的水平。细胞经BITC或BITC+乙酰半胱氨酸(NAC)处理24小时。
图20为流式细胞术检测人肺癌吉非替尼耐药细胞系PC9/AB2细胞内活性氧的水平。细胞经BITC或BITC+乙酰半胱氨酸(NAC)处理24小时。
图21为异硫氰酸苄酯对人肺癌顺铂耐药细胞系A549/DDP细胞内谷胱甘肽水平的影响。异硫氰酸苄酯浓度为5和10μM，作用时间为3-24小时。
图22为异硫氰酸苯乙酯对人肺癌顺铂耐药细胞系A549/DDP细胞内谷胱甘肽水平的影响。异硫氰酸苯乙酯浓度为5和10μM，作用时间为3-24小时。
图23为异硫氰酸酯对转录因子NFκB活性的调控。人肺癌顺铂耐药细胞系A549/DDP细胞转染pNFκB-luc质粒。PEITC和BITC浓度分别为10μM，作用时间20小时。
具体实施方式
下面结合具体实例对本发明作进一步的说明。
实施例1
异硫氰酸苄酯在制备防治耐药肿瘤药物的用途，异硫氰酸苄酯(BITC)的分子式为C6H5CH2NCS；结构式为：
所述耐药肿瘤为耐药肺癌，耐药肝癌，耐药食道癌，耐药胃癌，耐药结肠癌，耐药胰腺癌，耐药乳腺癌，耐药宫颈癌，耐药卵巢癌，耐药前列腺癌，耐药阴茎癌，耐药黑色素瘤，耐药脑瘤，耐药口腔肿瘤，耐药耳癌，耐药鼻咽癌和/或耐药舌癌。
实施例2
异硫氰酸苯乙酯在制备防治肿瘤耐药药物的用途，异硫氰酸苯乙酯(PEITC)的分子式为C6H5CH2CH2NCS；结构式为：
所述耐药肿瘤为耐药肺癌，耐药肝癌，耐药食道癌，耐药胃癌，耐药结肠癌，耐药胰腺癌，耐药乳腺癌，耐药宫颈癌，耐药卵巢癌，耐药前列腺癌，耐药阴茎癌，耐药黑色素瘤，耐药脑瘤，耐药口腔肿瘤，耐药耳癌，耐药鼻咽癌和/或耐药舌癌。
异硫氰酸苄酯和异硫氰酸苯乙酯加入药学可接收的辅料按常规方法制成各种剂型，如各种规格的液体注射剂，粉针注射剂，注射用乳剂，片剂，丸剂，胶囊剂，膏剂，霜剂，贴剂，擦剂，粉剂，喷雾剂，植入剂，滴剂，栓剂，软膏剂，糖果剂等。
异硫氰酸苄酯和异硫氰酸苯乙酯的给药途径包括各种给药途径：口服给药，注射给药，植入给药，腔内给药，舌下给药，肛门给药，透皮给药，内外敷等。
实施例3
异硫氰酸酯抑制多种耐药肿瘤细胞生长
我们选用人肺癌顺铂(cisplatin)敏感细胞系A549和顺铂耐药细胞系A549/DDP，及人肺癌吉非替尼(Gifitinib)敏感细胞系PC9和吉非替尼耐药细胞系PC9/AB2，通过MTT法，发现BITC和PEITC能有效抑制敏感及耐药细胞的生长，尤其对顺铂耐药细胞A549/DDP的生长抑制作用(IC50分别为8.8μM和13.7μM)比顺铂敏感细胞A549(IC50分别为14.1μM和17.6μM)更强，表明对耐药细胞具有选择性抑制作用。其中等生长抑制浓度见表1。图1-图4为BITC抑制细胞生长的剂量—生长曲线。图5-图8为PEITC抑制细胞生长的剂量—生长曲线。
表1异硫氰酸酯抑制肿瘤细胞生长的50％生长抑制浓度(IC50)
实施例4
异硫氰酸酯对肿瘤耐药相关基因的调控
通过定量PCR的方法，检测了BITC对顺铂耐药细胞A549/DDP和吉非替尼耐药细胞PC9/AB2中多药耐药蛋白multidrug resistant protein 1(MRP1)和药物代谢酶NAD(P)Hquinone oxidoreductase 1(NQO1)表达的影响。结果显示，BITC浓度为10μM时，作用4小时即能降低MRP1和NQO1的mRNA的表达水平(图9-图10)。
实施例5
异硫氰酸酯诱导肺癌耐药细胞凋亡
通过Annexin-V标记法，运用流式细胞术，检测了异硫氰酸酯诱导肺癌耐药细胞凋亡的作用。异硫氰酸苄酯和异硫氰酸苯乙酯浓度为10μM，作用时间为24小时。结果显示，BITC和PEITC可有效诱导肺癌耐药细胞凋亡。图11-1：A549/DDP细胞，对照；图11-2：A549/DDP细胞，BITC处理；图12-1：PC9/AB2细胞，对照；图12-2：PC9/AB2细胞，BITC处理。图13-1：A549/DDP细胞，对照；图13-2：A549/DDP细胞，PEITC处理；图14-1：PC9/AB2细胞，对照；图14-2：PC9/AB2细胞，PEITC处理。图15显示BITC诱导凋亡细胞的比例。图16显示PEITC诱导凋亡细胞的比例。
实施例6
异硫氰酸酯诱导肺癌耐药细胞周期停滞。
通过Propidium iodide染色，运用流式细胞术，检测了异硫氰酸酯对细胞周期的影响。研究显示BITC浓度为10μM时，作用24小时，可诱导细胞周期停滞，使细胞周期停滞在G2/M期，从而抑制细胞的生长。图17-1：A549/DDP细胞，对照；图17-2：A549/DDP细胞，BITC处理；图18-1：PC9/AB2细胞，对照；图18-2：PC9/AB2细胞，BITC处理。
实施例7
异硫氰酸酯提高细胞内活性氧的水平。
应用DCFH-DA荧光探针，运用流式细胞术，检测了细胞内活性氧(reactive oxygenspecies，ROS)的水平。异硫氰酸苄酯浓度为10μM，作用时间为24小时。研究发现，BITC提高细胞内活性氧的水平，引发氧化损伤。抗氧化剂乙酰半胱氨酸(N-acetyl cysteine，NAC)可有效保护细胞，降低异硫氰酸酯诱导的细胞内活性氧的水平。图19：A549/DDP细胞；图20：PC9/AB2细胞。
实施例8
异硫氰酸酯降低耐药细胞内谷胱甘肽glutathione(GSH)的水平
应用试剂盒检测了细胞内GSH的水平。异硫氰酸苄酯浓度为5和10μM，作用时间为3-24小时。BITC和PEITC明显降低A549/DDP细胞内谷胱甘肽的水平(图21，图22)。因谷胱甘肽是细胞内重要的还原剂，对维持胞内氧化-还原平衡起重要作用，谷胱甘肽水平的降低即造成氧化损伤，从而抑制细胞的生长
实施例9
异硫氰酸酯抑制转录因子的活性。
我们检测了异硫氰酸酯对转录因子NFκB转录活性的影响。通过运用荧光素酶报告基因的方法，将质粒pNFκB-luc转染到A549/DDP细胞中，检测了异硫氰酸酯对转录因子活性的影响。BITC和PEITC浓度为10μM，作用时间为20小时。结果显示BITC和PEITC抑制转录因子NFκB(图23)的活性。
上述实验结果表明，BITC和PEITC可有效抑制人肺癌耐药细胞的生长。BITC和PEITC是通过调控肿瘤耐药相关基因的表达，诱导细胞凋亡，引起细胞周期停滞，引发氧化损伤，调控转录因子等途径抑制肿瘤耐药细胞的生长。因BITC和PEITC具有此功能，故可作为有效成分制备具有抑制人肿瘤耐药细胞生长的药品、食品、保健品及化妆品。
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Claims (1)
1.异硫氰酸酯在制备防治耐药肿瘤药物的用途，所述异硫氰酸酯为异硫氰酸苄酯或异硫氰酸苯乙酯，所述异硫氰酸苄酯的分子式为C6H5CH2NCS；结构式为：
所述异硫氰酸苯乙酯的分子式为C6H5CH2CH2NCS；结构式为：
所述耐药肿瘤为耐药肺癌。
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