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1.
目的探讨三氧化二砷(As2O3)体外逆转人乳腺癌细胞多药耐药性的作用及机制。方法采用MTT法检测As2O3的细胞毒作用和处理前后耐药细胞对化疗药物的敏感性,用流式细胞仪检测细胞内阿霉素浓度,通过RT-RCR检测MDR1基因的表达。结果 As2O3在0.25mg/L以下剂量时对MCF-7和MCF-7/ADM耐药细胞株的抑制率均小于15%,半数抑制率(IC50)分别为1.01m/L和1.28mg/L,无细胞毒剂量0.2mg/L的As2O3能部分逆转MCF-7/ADM细胞对阿霉素的耐药性。同时无细胞毒剂量0.2mg/L的As2O3能使MCF-7/ADM细胞内阿霉素浓度明显增加,MDR1表达下降。结论 As2O3具有体外部分逆转人乳腺癌细胞多药耐药性的作用,可能与增加细胞内药物积累、下调MDR1表达有关。  相似文献   

2.
目的探讨三氧化二砷(As2O3)对胃癌细胞SGC7901/ADR阿霉素(ADM)耐药性的逆转作用和对GSTπ和TopoⅡ表达的影响。方法用MTT法检测As2O3的非细胞毒性浓度和SGC7901/ADR细胞对ADM的敏感性,用流式细胞仪检测细胞内药物浓度及用免疫组织化学法检测细胞GSTπ和TopoⅡ的表达。结果与结论0.4~0.8μmol.L-1As2O3对耐药细胞SGC7901/ADR无明显毒性(P<0.01),As2O3可下调GSTπ表达,提高SGC7901/ADR细胞内ADM浓度,部分逆转SGC7901/ADR细胞对ADM的耐药性。  相似文献   

3.
目的探讨三氧化二砷(As2O3)对肺腺癌耐药细胞株(A549/R)耐药性的逆转作用.方法采用四甲基偶氮唑蓝(MTT)法及荧光分光光度计分别检测As203的细胞毒性、A549/R细胞的药敏性及As203作用前后细胞内药浓的变化;采用生化方法检测A549/R细胞谷胱甘肽-S-转移酶(GSTs)活性,观察非细胞毒性剂量(0.15μmol·L-1)和低毒剂量(0.375 μmol·L-1)的As203对肺腺癌A549/R耐药细胞内GSTs活性的影响.结果As203在非细胞毒剂量下可显著降低耐药细胞对ADM的IC50值;As203作用后A549/R细胞内ADM积聚增加,其逆转倍数为2.3倍;A549/R细胞中GSTs活性增高,不同浓度的As203可降低GSTs活性;结论As203可通过降低GSTs活性而部分逆转A549/R细胞对ADM耐药.  相似文献   

4.
目的:板蓝根高级不饱和脂肪酸对肝癌耐药细胞株BEL-7404/ADM耐药逆转作用及机制研究。方法:MTT法观察药物对细胞的生长抑制作用;免疫组化法检测细胞P 糖蛋白(P-gp)和多药耐药相关蛋白(MRP)的表达;采用高效液相色谱法(HPLC)测定细胞内ADM的浓度。结果:耐药肝癌细胞株BEL-7404/ADM对多种化疗药物产生多药耐药性,耐药细胞P-gp和MRP的阳性率显著高于亲本细胞(P<0.01) ;板蓝根高级不饱和脂肪酸在非细胞毒剂量时与ADM合用后能逆转BEL 740 4/ADM对ADM的耐药性;ADM与板蓝根高级不饱和脂肪酸合用时,其细胞内ADM的含量较单独使用明显增高。结论:肝癌细胞株BEL-7404/ADM对多种化疗药物具有多药耐药性,其多药耐药性与P-gp和MRP过量表达有关;板蓝根高级不饱和脂肪酸在非细胞毒剂量时能逆转BEL-7404/ADM对ADM的耐药性,其逆转作用可能与降低P-gp药物外排功能、增加细胞内药物浓度有关  相似文献   

5.
目的运用血清药理学方法,体外研究温下方对A549/DDP细胞多药耐药的逆转作用及机制。方法正常血清及不同浓度的温下方含药血清作用于A549/DDP细胞,四甲基偶氮唑蓝(MTT)法检测温下方含药血清对A549/DDP细胞的逆转作用;运用免疫荧光技术,激光共聚焦显微镜及流式细胞仪检测肺耐药相关蛋白(LRP)、多药耐药相关蛋白(MRP)和P-糖蛋白(P-gp)的表达。结果温下方含药血清能明显逆转A549/DDP细胞的多药耐药,增敏倍数为2~2.5倍。并可明显降低P-gp、LRP、MRP蛋白表达。结论温下方通过降低P-gp、LRP、MRP的表达以增强A549/DDP对化疗药的敏感性,逆转肺腺癌细胞的多药耐药。  相似文献   

6.
目的 考察黄芩苷对人肝癌耐药细胞Bel-7402/ADM 多药耐药性的逆转机制.方法 MTT法考察Baicalin对人肝癌多药耐药细胞的逆转作用.结果 Baicalin逆转Bel-7402/ADM多药耐药性的机制可能与抑制MDR1部分基因产物P-gp、MRP、GSH/GST的表达和诱导细胞凋亡有关.结论 Baicalin可能通过抑制MDR1部分基因产物P-gp、MRP、GSH/GST的表达和诱导细胞凋亡逆转Bel-7402/ADM的多药耐药性.  相似文献   

7.
红霉素逆转人肝癌细胞BEL-7402多药耐药性的研究   总被引:4,自引:1,他引:3  
目的 研究红霉素 (ERY)对BEL 740 2细胞 (人肝癌细胞 )多药耐药性的逆转作用。方法 将BEL 740 2细胞连续培养在含阿霉素 (ADM )的培养液中诱导耐药细胞株BEL 740 2 /ADM ,用cell ELASA法检测细胞膜表面P gp的表达 ,细胞毒试验采用MTT法 ,用荧光分光光度法测定细胞内ADM浓度。结果 BEL 740 2 /ADM细胞表面P gp高度表达 ,除对ADM耐药外 ,对长春新碱 (VCR)和丝裂霉素(MMC)也有不同程度的交叉耐药 ;ERY可增强ADM、VCR、MMC对BEL 740 2 /ADM细胞的增殖抑制作用 ,可增加BEL 740 2 /ADM细胞内ADM的浓度而对细胞膜表面P gp的表达没有影响。结论 ERY通过竞争性地饱和BEL 740 2 /ADM细胞表面P gp通道 ,使细胞内药物外排减少、浓度增加 ,从而发挥对BEL 740 2 /ADM细胞多药耐药性的逆转作用  相似文献   

8.
三氧化二砷对人肺腺癌细胞凋亡及LRP、MRP基因表达的影响   总被引:1,自引:0,他引:1  
林浩  韩冰  洪管秋 《海峡药学》2010,22(1):92-94
目的探讨三氧化二砷(As2O3)对人肺腺癌细胞凋亡和LRP、MRP基因表达的影响。方法选用人肺腺癌A549细胞株,运用体外细胞培养法,MTT法,流式细胞术检测As2O3对人肺腺癌的抑制和诱导凋亡作用;用逆转录-聚合酶链反应(RT-PCR)方法检测LRP、MRP mRNA的表达。结果As2O3对人肺腺癌A594细胞具有抑制作用.其抑制率呈时间-剂量依赖关系。不同浓度的As2O3均可诱导凋亡。1.0μmol·L^-1、2.0μmol·L^-1。浓度的As2O3可下调LRP、MRP mRNA的表达。结论As2O3具有诱导人肺腺癌细胞凋亡的作用,其机制与其下调LRP、MRP mRNA的表达密切相关。  相似文献   

9.
丹参酮Ⅱ_A逆转多药耐药的体外效应研究   总被引:1,自引:0,他引:1  
《中国药房》2015,(25):3488-3490
目的:研究丹参酮ⅡA逆转多药耐药的体外效应。方法:以0[仅20 mg/L多柔比星(ADM)或顺铂(DDP),阴性对照]、5mg/ml丹参酮ⅡA(联合20 mg/L ADM或DDP)培养人乳腺癌耐ADM(MCF-7/ADM)细胞、人肺癌耐DDP(A549/DDP)细胞24、48 h后,采用MTT法测定细胞活力;聚合酶链反应(PCR)法测定细胞中细胞周期控制蛋白CDC25A、细胞周期蛋白依赖性激酶2(CKD2)m RNA表达。结果:与阴性对照比较,丹参酮ⅡA作用于MCF-7/ADM、A549/DDP细胞24、48 h后细胞活力减弱,细胞中CDC25A、CKD2 m RNA表达减弱,差异有统计学意义(P<0.01)。结论:丹参酮ⅡA联合ADM或DDP能够抑制MCF-7/ADM和A549/DDP的细胞活力,减弱细胞中CDC25A、CKD2 m RNA表达,具有一定的逆转恶性肿瘤多药耐药的作用。  相似文献   

10.
目的:板蓝根高级不饱和脂肪酸对肝癌耐经细胞株BEL-7404/ADM耐药逆转作用主机制研究。方法:MTT法观察药物对细胞的生长抑制作用;免疫组化法检测细胞P-糖蛋白(P-gp)和多药耐药相关蛋白(MRP)的表达;采用高效液相色谱法(HPLC)测定细胞内ADM的浓度。结果:耐药肝癌细胞株BEL-7404/ADM对多种化疗药物产生多药耐药性,耐药细胞P-gp和MRP的阳性率显著高于亲本细胞(P<0.01);板蓝根高级不饱和脂肪酸在非细胞毒剂量时与ADM合用后能逆转BEL-7404/ADM对ADM的耐药性;ADM与板蓝根高级不饱和脂肪酸合用时,其细胞内ADM的含量较单独使用明显增高。结论:肝癌细胞株BEL-7404/ADM对多种化疗药物具有多药耐药性,其多药耐药性与P-gp和MRP过量表达有关;板蓝根高级不饱和脂肪酸在非细胞毒剂量时能逆转BEL-7404/ADM对ADM的耐药性,其逆转作用可能与降低P-gp药物外排功能、增加细胞内药物浓度有关。  相似文献   

11.
耐阿霉素人骨肉瘤细胞株的建立及其耐药机制探讨   总被引:1,自引:0,他引:1  
目的诱导并建立耐阿霉素(ADM)的人骨肉瘤细胞株并探讨其耐药机制。方法采用逐步增加药物剂量冲击诱导方法诱导人成骨肉瘤原代Saos-2细胞株;MTT法检测原代与耐药细胞株对ADM、顺铂(DDP)、甲氨蝶呤(MTX)、异环磷酰胺(IFO)、表柔比星(EPI)、比柔比星(THP)、紫杉醇(Paclitaxel,PTX)药物敏感性;利用光学显微镜、透射电镜观察细胞形态及超微结构变化;RT-PCR和IHC法分别检测多药耐药基因1(MDR1)、多药耐药相关蛋白(MRP)基因及其相应蛋白(P-gp)、MRP的表达。结果经167d的诱导,建立Saos-2/ADM1、Saos-2/ADM4细胞株,其对ADM的耐药指数分别为原代细胞株的49.8和74.6倍;耐药细胞株对MTX、EPI、THP、PTX亦产生不同程度的交叉耐药(P<0.05),对DDP仍然敏感(P>0.05);光镜观察Saos-2/ADM1、Saos-2/ADM4细胞株细胞体积增大,多核现象较原代Saos-2细胞株明显增加;透射电镜显示Saos-2/ADM1、Saos-2/ADM4细胞株表面突起较原代Saos-2细胞株减少、且核仁增大增多;细胞生长曲线显示耐药细胞株增殖能力下降。MDR1mRNA、MRPmRNA和P-gp、MRP在各耐药细胞株表达阳性。结论MDR1 mRNA、MRP mRNA及其相应蛋白参与了耐药细胞株耐药的形成,这些骨肉瘤耐药细胞株为进一步研究骨肉瘤耐药特征及逆转方法打下了基础。  相似文献   

12.
Arsenic trioxide (As(2)O(3)) has been reported to have potent antitumor effects in vitro and in vivo by inducing cell death via cell cycle arrest and apoptosis in leukemia cells, but the mechanisms of As(2)O(3)-mediated cell death are not fully understood. In this study, we provided in vitro evidence that As(2)O(3) was a potent inducer of autophagy in leukemia K562 and its drug-resistant line K562/ADM cells. As(2)O(3) significantly activated autophagic cell death (programmed cell death type II) in leukemia cell lines. Numerous large cytoplasmic inclusions, abundant autophagic vacuoles, phagocytizing cytoplasm and organelles were observed in As(2)O(3)-treated cells using electron microscope. MDC-labeled autophagic vacuoles were observed by fluorescent inverted phase contrast microscopy and the enhanced MDC fluorescent staining was detected by flow cytometry in As(2)O(3)-treated cells. Furthermore, real-time quantitative RT-PCR revealed that the expression levels of Beclin-1 and LC3 genes, which play key roles in autophagy, increased in As(2)O(3) treated samples than in controls, indicating that autophagy can potentially be involved in the antitumor properties of As(2)O(3). The expression level of Bcl-2 gene, an anti-apoptotic molecule, decreased in As(2)O(3) treated samples than in controls, suggesting that Bcl-2 may be involved in accumulating Beclin-1 and triggering autophagic cell death in As(2)O(3)-treated leukemia cells. Western blotting also showed that As(2)O(3) up-regulated Beclin-1. Altogether, our data provide direct evidence that autophagic cell death is critical for the effects of As(2)O(3) on acute myelogenous leukemia cells.  相似文献   

13.
As_2O_3对人非小细胞肺癌细胞株的增殖抑制及其分子机制   总被引:1,自引:0,他引:1  
目的观察三氧化二砷(As_2O_3)对非小细胞肺癌腺癌细胞株(A549)的增殖抑制作用及其分子机制。方法体外培养的A549细胞经3μmol/L的As2O3处理5d后,观察细胞形态学、增殖动力学、细胞周期分布及肿瘤相关基因表达改变,并以全反式维甲酸及顺铂作为对照。结果A549细胞经As_2O_3处理后,细胞生长明显减慢,集落形成率显著降低。FCM细胞周期分析:S期细胞显著减少,G0/G1期细胞则明显增加。As_2O_3可使细胞p53、p21表达显著升高而CDKN2明显降低。结论As_2O_3对A549细胞增殖具有显著抑制作用,其分子机制可能是As_2O_3能显著上调p53、p21表达和下调CDKN2的表达而抑制DNA的合成。  相似文献   

14.
Overexpression of P-glycoprotein (Pgp) and multidrug resistance protein 1 (MRP1) by tumors results in multidrug resistance (MDR) to structurally unrelated anti-tumor agents. HZ08, a chiral compound, was a newly synthesized tetraisohydroquinoline derivative to reverse Pgp and MRP1 mediated MDR. In present studies, R, S-HZ08 and their racemate reversed the resistance to adriamycin and vincristine of adriamycin-selected human leukemia (K562/ADM) cells that overexpress Pgp. R, S-HZ08 and their racemate modulated adriamycin cytotoxicity when R, S-HZ08 and their racemate were removed 12 h prior to the cytotoxicity assay. In addition, R, S-HZ08 and their racemate increased intracellular accumulation of Rhodamine123 in Caco-2 cells that overexpress Pgp. Furthermore, using a DNA content analysis and an annexin V binding assay, R, S-HZ08 and their racemate effectively reversed the resistance to adriamycin-induced apoptosis in K562/ADM cells. R, S-HZ08 and their racemate also moderately reversed the resistance to adriamycin and vincristine of MCF-7/ADM cells that overexpress MRP1. However, R, S-HZ08 and their racemate hardly affected intracellular glutathione (GSH) levels and glutathione S-transferase (GST) activities in MCF-7/ADM cells. The result showed that R, S-HZ08 and their racemate possibly reverse MDR1 mediated multidrug resistance by a direct interaction with MRP1, not interaction with MRP1 via GSH. Thus, R, S-HZ08 and their racemate should be useful for treating patients with tumors that overexpress both Pgp and MRP1.  相似文献   

15.
KF22678, a novel thioester derivative of leinamycin with the 1-oxo-1,2-dithiolane-3-one moiety, was examined for anti-tumor activity, toxicity in mice and activation mechanism. KF22678 showed a broad antitumor spectrum against human carcinoma xenografts (lung, colon, ovary and prostate). The efficacy of KF22678 was significantly higher than that of cisplatin. KF22678 exhibited low cross-resistance against various drug-resistant cell lines of MDR1 or MRP overexpressing human tumors, and, in addition, exhibited more potent antitumor activity in vivo than ADM against A2780/ADM and KB/MRP xenograft. DL-Buthionine sulfoximine (BSO) pretreatment significantly reduced intracellular glutathione (GSH) level in human lung carcinoma A549 cells, leading to decrease in the cytotoxicity of KF22678, whereas the cytotoxicity of melphalan was augmented by BSO pretreatment. DNA single-strand breaks (SSB) were observed in A549 cells treated with KF22678 and bleomycin. DNA SSB induced by KF22678 was greatly reduced in the presence of BSO in the cells, whereas DNA SSB induced by bleomycin was not. In addition, the antitumor activity of KF22678 against BSO-pretreated human lung carcinoma PC-9 tumor was significantly decreased. These results suggest that the activation of KF22678 by intracellular GSH might be important for DNA SSB and antitumor activity in vitro and in vivo.  相似文献   

16.
A newly synthesized taxoid originally from the Japanese yew Taxus cuspidata, 5-O-benzoylated taxinine K (BTK) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein (MRP)-mediated multidrug resistance. BTK reversed the resistance to paclitaxel, doxorubicin (ADM), and vincristine (VCR) of KB-8-5 and KB-C2 cells that overexpress P-gp by directly interacting with P-gp. BTK also moderately reversed the resistance to ADM of KB/MRP cells that overexpress MRP. However, BTK neither inhibited the transporting activity of MRP nor reduced intracellular glutathione levels in KB/MRP cells. BTK shifted the distribution of ADM in KB/MRP cells from punctate cytoplasmic compartments to the nucleoplasm and cytoplasm by inhibiting acidification of cytoplasmic organelles. These two functions of BTK make it able to reverse both P-gp- and MRP-mediated MDR. BTK in combination with ADM should be useful for treating patients with tumors that overexpress both P-gp and MRP.  相似文献   

17.
钱钧强  ;孙蓓  ;房志仲 《中国药房》2014,(47):4433-4436
目的:研究荜茇酰胺对人肺癌A549/顺铂(DDP)细胞耐药性的逆转作用。方法:A549/DDP细胞经0、20、30μmol/L荜茇酰胺作用48 h后,用MTS法检测肿瘤细胞抑制率;流式细胞术检测肿瘤细胞凋亡、细胞周期、P-糖蛋白(P-gp)表达和肿瘤细胞内罗丹明Rht123含量的变化;Western blotting法检测多药耐药基因(MDR)1、多药耐药相关蛋白(MRP)1、DNA拓扑异构酶(Top)Ⅱ、谷胱甘肽S-转移酶(GST)-π、凋亡抑制蛋白Survivin、周期蛋白依赖性蛋白激酶(CDK)1和蛋白激酶(PK)Cζ蛋白表达;实时荧光聚合酶链反应(RT-PCR)法检测MDR1、MRP1、Top-II、GST-π、Survivin和CDK1 m RNA表达;酶标仪检测含半胱氨酸的天冬氨酸蛋白水解酶(Caspase)-3、8活性。结果:A549/DDP细胞经0、20、30μmol/L荜茇酰胺作用48 h后,DDP对肿瘤细胞增殖的抑制率明显升高;与0μmol/L比较,20、30μmol/L荜茇酰胺作用48 h后,DDP导致的细胞凋亡率和G2期/M期明显升高,P-gp表达明显减弱,Rh-123浓度明显增加,MDR1、MRP1、Top-II、GST-π、Survivin、CDK1和PKCζ蛋白表达明显减弱,MDR1、MRP1、Top-Ⅱ、GST-π、Survivin、CDK m RNA表达明显减弱,Caspase-3、8的活性明显增强。结论:荜茇酰胺可逆转人肺癌A549/DDP细胞DDP耐药性,可能与其调节多药耐药相关基因表达有关。  相似文献   

18.
Chemoresistance remains the major obstacle to successful therapy of cancer. In order to understand the mechanism of multidrug resistance (MDR) that is frequently observed in lung cancer patients, here we studied the contribution of MDR-related proteins by establishing lung cancer cell lines with acquired resistance against etoposide. We found that human H460 lung cancer cells responded to etoposide more sensitively than A549 cells. Among MDR-related proteins, the expression of p-glycoprotein (Pgp) and lung resistance protein (LRP) were much higher in A549 cells compared with that in H460 cells. When we established H460-R1 and -R2 cell lines by progressive exposure of H460 cells to increasing doses of etoposide, the response against etoposide as well as doxorubicin was greatly reduced in R1 and R2 cells, suggesting MDR induction. Induction of MDR was not accompanied by a decrease in the intracellular accumulation of etoposide and the expression of MDR-related proteins that function as drug efflux pumps such as Pgp and MRP1 was not changed. We found that the acquired resistance paralleled an increased expression of LRP in H460 cells. Taken together, our data suggest the implicative role of LRP in mediating MDR in lung cancer.  相似文献   

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