CN111249263A - 麦普替林在逆转胃癌多药耐药性中的应用 - Google Patents
麦普替林在逆转胃癌多药耐药性中的应用 Download PDFInfo
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Abstract
本发明涉及医药技术领域,具体涉及麦普替林在制备逆转胃癌耐药性的药物中的用途,麦普替林在制备增加依托泊苷预防和/或治疗胃癌的敏感性的药物中的用途,麦普替林在制备预防和/或治疗胃癌的药物中的用途,和麦普替林和依托泊苷的组合在制备预防和/或治疗胃癌的药物中的用途。
Description
技术领域
本发明涉及医药技术领域,具体涉及麦普替林在制备逆转胃癌耐药性的药物中的用途,以及麦普替林在增加依托泊苷对耐药性胃癌治疗敏感性的药物中的用途。
背景技术
胃癌是我国最常见的消化道恶性肿瘤,发病率和死亡率很高,治疗上以手术为主,化学治疗时术后综合治疗的主要手段。然而,多药耐药性(MDR)是胃癌治疗失败的主要原因,因此,逆转胃癌细胞的多药耐药性有助于提高胃癌的治疗效果和患者的生存率。
麦普替林,是一种四环类抗抑郁药,抗抑郁效果与丙米嗪,阿米替林相似,但奏效快、副作用少服药后精神症、对环境的适应能力、及自制力均有改善,安定作用睡眠改善,用于迟钝型抑郁症,也适用于激越型抑郁症,有抗组胺及抗胆碱作用亦用于疾病或精神因素引起的焦虑、抑郁症。现有技术已知多种三环或四环抗抑郁药具有抗癌活性,刘汀等(解剖科学进展,22(3):276-278.)报道了麦普替林促进黑色素瘤细胞凋亡,抑制黑色素瘤细胞增殖、迁移和侵袭的作用。Shu-Shong Hsu等(Clinical and Experimental Pharmacology and Physiolog, 2004(31):444-449.)报道了麦普替林增加前列腺癌细胞中Ca[2+]浓度和降低前列腺癌细胞增殖的作用。Cloonan SM.等(Leuk Lymphoma, 2010(51):523-539)报道了麦普替林对Burkitt淋巴瘤的抗增殖作用。
但是,没有现有技术记载麦普替林对胃癌细胞,特别是多药耐药性胃癌细胞的抑制作用。更没有现有技术记载麦普替林逆转多药耐药性胃癌的耐药性,以及提高胃癌治疗剂依托泊苷对多药耐药性胃癌治疗敏感性的作用。
发明内容
鉴于此,本发明要解决的技术问题是提供一种基于麦普替林逆转胃癌多药耐药性的问题。
本发明一方面提供一种麦普替林在制备逆转胃癌耐药性的药物中的用途。
第二方面,本发明提供一种麦普替林在制备预防和/或治疗胃癌的药物中的用途。
进一步地,所述胃癌是多药耐药性胃癌。
进一步地,所述胃癌对依托泊苷耐药。
第三方面,本发明提供一种麦普替林在制备增加依托泊苷预防和/或治疗胃癌的敏感性的药物中的用途。
进一步地,所述麦普替林逆转多药耐药胃癌对依托泊苷的耐药性。
第四方面,麦普替林和依托泊苷的组合在制备预防和/或治疗胃癌的药物中的用途。
进一步地,所述胃癌是多药耐药性胃癌。
本发明的结果表明,麦普替林不但对胃癌细胞和多药耐药性胃癌细胞具有剂量依赖的生长抑制作用。而且,能够逆转耐药细胞株SGC7901/mdrl对依托泊苷的耐药性。无明显细胞毒性剂量(IC10)的麦普替林能够显著逆转胃癌多药耐药细胞SGC7901/mdrl对依托泊苷的耐药性,两者联用能够提高依托泊苷对胃癌细胞株SGC7901,特别是多药耐药胃癌细胞株SGC7901/mdrl的治疗敏感性,将依托泊苷对SGC7901/mdrl的IC50从22.08mg·L-1降低至10.08 mg·L-1,逆转倍数达到2.19倍,相对逆转率约为85.53%。
附图说明:
图1 麦普替林对SGC7901/mdrl细胞抑制率(%)的标准曲线(1A)和麦普替林对SGC7901细胞抑制率(%)的标准曲线(1B)。
图2 依托泊苷对SGC7901/mdrl细胞抑制率(%)的标准曲线(2A)和依托泊苷SGC7901细胞抑制率(%)的标准曲线(2B)。
图3 麦普替林和依托泊苷的组合对SGC7901/mdrl细胞抑制率(%)的标准曲线。
具体实施方案
下面结合具体实施例对本发明做进一步阐述,但本发明并不限于以下实施例。
实施例1 麦普替林对胃癌耐药性细胞SGC7901/mdrl依托泊苷耐药性的影响
1 材料与方法
1.1 主要试剂
麦普替林(maprotiline)购自诺华制药有限公司,依托泊苷(Etoposide,VP-16) (辰欣药业股份有限公司); 四甲基偶氮唑蓝(MTT)购自美国Sigma公司,二甲基亚砜( dimethylsulfoxide,DMSO) 购自美国Sigma 公司;全自动酶标仪(美国Bio-Rad公司),流式细胞仪(美国BD公司)。
1.2细胞株与培养液
SGC7901 细胞由本实验室保存,高表达mdr1的SGC7901 细胞( SGC7901/mdrl) 为本实验室构建。以含体积分数10%胎牛血清RPMI1640完全培养基在37 ℃、体积分数5% 的CO2饱和湿度条件下培养,传代时以2.5g·L -1胰蛋白酶消化。麦普替林于实验前用DMSO 配成10 mg·L-1,-20 ℃保存,用时以培养基稀释成所需浓度。依托泊苷用注射用水稀释成2 mg·L-1,-20 ℃保存,用时以培养基稀释成所需浓度。
1.3 MTT法测定麦普替林逆转SGC7901 /mdr1细胞依托泊苷耐药性的浓度
将培养的SGC7901和SGC7901 /mdr1细胞浓度调至2 × 108 L-1,加入96 孔培养板,每孔200 μL,培养24 h。
实验分别分成3组:
空白组:仅加入培养基,不接种细胞;
对照组:加培养基并接种细胞;
实验组:分别加入新培养基和相应质量浓度的麦普替林( 37.5、75.0、150.0、300.0、600. 0 mg·L -1 )。
上述各组培养48 h,倾尽培养液,每孔加终质量浓度0.5 mg·L -1的MTT稀释液200 μL,避光培养4 h,吸出上清液,每孔加DMSO 200 μL,避光微量振荡器振摇20 min,待完全溶解,酶标仪测定570 nm 处吸光度(OD) 值。实验重复3 次。
肿瘤细胞抑制率=[(对照组OD值-空白组OD值)-(实验组OD值-空白组OD值)]/ (对照组OD值-空白组OD值)*100%。
用肿瘤细胞抑制率和麦普替林的终浓度绘制抑制率和浓度曲线,计算麦普替林的IC50和IC10。
1.4 MTT法测定依托泊苷对SGC7901 /mdr1和SGC7901细胞IC50和耐药倍数
SGC7901 /mdr1和SGC7901细胞处理方法同上。
实验分为3组:
空白组:仅加入培养基,不接种细胞;
对照组:加培养基并接种细胞;
实验组: 将贴壁后的SGC7901和SGC7901 /mdr1细胞分别加入3.125、6.25、12.5、25、50mg·L-1的依托泊苷;
肿瘤细胞抑制率=[(对照组OD值-空白组OD值)-(实验组OD值-空白组OD值)]/ (对照组OD值-空白组OD值)*100%。
依托泊苷对SGC7901 /mdr1耐药倍数=依托泊苷对SGC7901 /mdr1细胞的IC50/依托泊苷对SGC7901 细胞的IC50。
1.5 MTT法测定麦普替林对耐药细胞SGC7901 /mdr1 的逆转作用
细胞培养以及实验方法同上。
实验分组为:
空白组:仅加入培养基,不接种细胞
对照组:SGC7901 /mdr1细胞培养基不加入任何药物;
实验组:SGC7901 /mdr1 细胞培养基中加入无明显细胞毒浓度的麦普替林(IC10剂量)和由1.4 确定的不同浓度的依托泊苷。
肿瘤细胞抑制率= [(对照组OD值-空白组OD值)-(实验组OD值-空白组OD值)]/ (对照组OD值-空白组OD值)*100%。
用肿瘤细胞抑制率和依托泊苷的终浓度计算IC50,进而计算耐药逆转倍数=依托泊苷对SGC7901 /mdr1的IC50/实验组IC50和相对逆转率=[(依托泊苷对SGC7901 /mdr1的IC50-实验组IC50 ) /(依托泊苷对SGC7901 /mdr1的IC50-依托泊苷对SGC7901的IC50)]。
1.6统计分析
应用SPSS 19.0软件进行统计处理,计量数据以均数±标准差( ± s) 表示,两样本均数比较采用t 检验,多样本均数比较采用方差分析,方差不齐时进行变量转换。P<0.05 为显著性差异,P<0.01为极显著性差异。
2 结果
2.1 麦普替林对SGC7901 /mdr1 细胞的耐药逆转浓度
SGC7901 /mdr1和SGC7901 细胞经不同浓度麦普替林作用48 h 后均有一定增殖抑制,呈剂量依赖关系,不同浓度麦普替林之间有显著性差异 ( P<0. 05 ) ;通过浓度-抑制率曲线,计算麦普替林对SGC7901 /mdr1 的 IC50为310.76mg·L-1,对SGC7901的IC50为280.84 mg·L-1 ,两者之间有显著性差异( P<0. 05 ) 。麦普替林对SGC7901 /mdr1的IC10为52.50 mg·L-1,对SGC7901 细胞IC10为50.6 mg·L-1,两者之间没有统计学差异 ( P> 0.05) ,取二者平均值51.55mg·L-1作为麦普替林对SGC7901 /mdr1细胞的耐药逆转质量浓度(图1A,图1B)。
2.2 依托泊苷对SGC7901 /mdr1和SGC7901细胞IC50和耐药倍数
通过浓度-抑制率曲线,计算依托泊苷对SGC7901 /mdr1和SGC7901细胞IC50分别为22.08mg·L-1和8.05 mg·L-1,耐药倍数为2.74倍(图2A,图2B)。
2.3 麦普替林对耐药细胞SGC7901 /mdr1的耐药逆转
通过浓度-抑制率曲线,计算不同浓度的依托泊苷与51.55 mg·L-1的麦普替林共培养后发现,依托泊苷对SGC7901 /mdr1的生长抑制率随依托泊苷的浓度升高而升高,IC50为10.08 mg·L-1(图3),麦普替林对耐药细胞SGC7901 /mdr1 的耐药逆转倍数约为2.19倍,相对逆转率约为85.53%。
以上结果表明,无细胞毒剂量的麦普替林能够逆转依托泊苷抗耐药性胃癌细胞株SGC7901 /mdr1的耐药性,将依托泊苷对SGC7901 /mdr1的IC50从22.08mg·L-1降低到10.08 mg·L-1,有效提高了依托泊苷的治疗敏感性。
上述详细说明是针对本发明其中之一可行实施例的具体说明,该实施例并非以限制本发明的专利范围,凡未脱离本发明所为的等效实施或变更,均应包含于本发明技术方案的范围内。
Claims (8)
1.麦普替林在制备逆转胃癌耐药性的药物中的用途。
2.麦普替林在制备预防和/或治疗胃癌的药物中的用途。
3.如权利要求2所述的用途,其特征在于,所述胃癌是多药耐药性胃癌。
4.如权利要求3所述的用途,其特征在于,所述胃癌对依托泊苷耐药。
5.麦普替林在制备增加依托泊苷预防和/或治疗胃癌的敏感性的药物中的用途。
6.如权利要求5的用途,其特征在于,所述麦普替林逆转多药耐药性胃癌对依托泊苷的耐药性。
7.麦普替林和依托泊苷的组合在制备预防和/或治疗胃癌的药物中的用途。
8.如权利要求8所述的用途,其特征在于,所述胃癌是多药耐药性胃癌。
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