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排序方式: 共有1097条查询结果,搜索用时 31 毫秒
1.
《药学学报(英文版)》2020,10(5):799-811
Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors. 相似文献
2.
《药学学报(英文版)》2020,10(2):327-343
Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer. 相似文献
3.
4.
OBJECTIVES: Previous studies have shown that pingyangmycin (PYM; bleomycin A5) can induce two distinct modes of cell death (necrosis, apoptosis). At high concentrations, PYM can be considered as an apoptosis mimetic drug. In this study, we explored the possibility that the membrane-modifying agent verapamil might affect the transport function of PYM through the plasma membrane, resulting in inducing apoptosis of tumor cells at low concentration of PYM. METHODS: Cytotoxicity, flow cytometry and DNA fragmentation assays were used to detect the interaction of verapamil and PYM in human oral carcinoma cell line KB cells. RESULTS: Our results indicated that verapamil can enhance the cytotoxicity of PYM against KB cells with the non-toxic doses (P<0.05). The cell viability at a concentration of 500 microg ml-1 of PYM was 35+/-2% compared with control and 10 microg ml-1 verapamil decreased the cell viability lower to 28+/-1%. In addition, because of the synergistic effect of verapamil, KB cells apoptosis was found to be induced when treated with a lower concentration of PYM (50 microg ml-1) for 24 h by flow cytometry and DNA fragmentation assays. CONCLUSIONS: Verapamil was found to enhance PYM-induced cytotoxicity and apoptosis in KB cells. The responsiveness of PYM might be explained by the effective accumulation of PYM by verapamil in KB cells mediated by the inhibition of PYM efflux function of the cells. 相似文献
5.
目的:观察VAMP方案加维拉帕米或环孢菌素A逆转治疗难治性ALL的疗效。方法:选择原发和继发耐药的ALL患者13例,采用VAMP方案加维拉帕米或环孢菌素A逆转体内、外研究。结果:13例ALL中7例达CR,3例达PR,3例无效。体外VAMP方案加VRP或CsA可有效逆转耐药。结论:采用VAMP方案加维拉帕米或环孢菌素A逆转治疗难治性ALL,可取得较好的疗效,为争取移植治疗创造了条件。 相似文献
6.
Robert P. Lanza MD David K.C. Cooper MB PhD Christiaan N. Barnard MD PhD DSc 《The American journal of emergency medicine》1984,2(6):481-485
There has been mounting speculation that calcium antagonists may be useful in reducing or preventing brain damage after cardiopulmonary resuscitation. To test the clinical usefulness of these agents in averting such damage, high-dose verapamil was administered to baboons and pigs after partial cerebral ischemia for varying periods of time. In Group A baboons and pigs, the major aortic branches supplying the carotid and vertebral circulations were clamped for periods ranging from 15 to 150 minutes, and neurological recovery was observed. In Group B, verapamil hydrochloride 0.7 mg/kg was given by intravenous infusion after similar periods of arterial occlusion. The administration of verapamil did not lead to any clinically improved neurological outcome. The use of verapamil after prolonged periods of partial cerebral ischemia did not improve neurological recovery in baboons and pigs. 相似文献
7.
维拉帕米-普鲁卡因合剂防治危重手术后急性呼吸窘迫综合征的临床观察 总被引:8,自引:1,他引:8
目的观察维拉帕米普鲁卡因合剂(维普合剂)防治危重患者手术后急性呼吸窘迫综合征(ARDS)的效果,探讨适宜推广应用防治ARDS的简便、实用、价廉方法。方法符合ARDS高危因素的各科危重手术患者150例,在常规基础综合治疗基础上随机分为3组:维普合剂组给予质量分数为5%的葡萄糖500ml+普鲁卡因1250mg+维拉帕米10mg;普鲁卡因组给予5%葡萄糖500ml+普鲁卡因1250mg;对照组仅给予5%葡萄糖500ml。3组均以0.5ml·h-1·kg-1持续静脉滴注,确诊急性肺损伤(ALI)或ARDS后,维普合剂组和普鲁卡因组的普鲁卡因和维拉帕米剂量均加倍,滴速不变。均应用金科威UT4000F持续无创监测血压(BP)、心电图(ECG)、脉搏血氧饱和度(SpO2)、呼吸及体温,间断测定动脉血气分析和外周血常规。依据全身炎症反应综合征(SIRS)、ALI与ARDS诊断标准确定诊断,并进行SIRS评分和急性生理学与慢性健康状况(APACHE)评分。结果维普合剂组、普鲁卡因组和对照组24hSIRS确诊数分别为11例、26例和42例,组间比较差异均有显著性(P均<0.01);术后72h3组ALI确诊数分别为4例、7例和19例,维普合剂组与普鲁卡因组组间比较差异无统计学意义,维普合剂组和普鲁卡因组与对照组比较差异均有显著性(P均<0.01);术后2周仅对照组有12例确诊ARDS,其中5例并发多器官功能衰竭后死亡, 相似文献
8.
Farshid Davoodi Abbas Raisi Asghar Rajabzadeh Mohammad Hassan Hablolvarid Amir Zakian 《Andrologia》2020,52(2):e13479
In this research, the impacts of combined administration of verapamil and heparin on testicular torsion damage were examined. In this experimental study, 30 sexually mature male Wistar albino rats were divided into five equal groups haphazardly (n = 6): Group 1 was the sham group. In group 2, a 2-hr testicular torsion was induced, and thereafter, detorsion was done. Rats in group 3 and group 4 experienced an identical surgical procedure like group 2, but verapamil and heparin were administered in 0.3 mg/kg and 800 IU/kg doses respectively, and in group 5, a combination of verapamil and heparin were administered. Intraperitoneal drug injection in all treatment groups was done 30 min before testicular detorsion. Testicular torsion significantly changed sperm parameters, oxidative stress biomarkers and Cosentino's histological score compared to the sham group (p < .05). All treatment groups reduced testicular damage by decreasing oxidative stress and improving sperm parameters, but heparin and co-administration of verapamil and heparin were significantly better than verapamil injection alone. However, heparin injected group was more effective than other treatment groups (p < .05). Overall, an anticoagulant like heparin is more effective than a calcium channel blocker such as verapamil, and it is more likely to reduce testicular torsion injuries. 相似文献
9.
Nogami A 《Pacing and clinical electrophysiology : PACE》2011,34(5):624-650
Purkinje-related monomorphic ventricular tachycardias (VTs) can be classified into four distinct groups: (1) verapamil-sensitive left fascicular VT, (2) Purkinje fiber-mediated VT post infarction, (3) bundle branch reentry (BBR) and interfascicular reentry VTs, and (4) focal Purkinje VT. There are three subtypes of fascicular VTs: (1) left posterior fascicular VT with a right bundle branch block (RBBB) configuration and superior axis; (2) left anterior fascicular VT with an RBBB configuration and right-axis deviation; and (3) upper septal fascicular VT with a narrow QRS configuration. The mechanism of the fascicular VT is macroreentry. While the antegrade limb of the circuit is a midseptal abnormal Purkinje fiber in the anterior and posterior fascicular VTs, the antegrade limb of the upper septal fascicular VT is both the anterior and posterior fascicles, and the retrograde limb is a midseptal abnormal Purkinje fiber. Purkinje fiber-mediated VT post infarction also exhibits verapamil sensitivity, and the surviving muscle bundles within the myocardium and Purkinje system are components of the reentry circuit. BBR-VT and interfascicular reentry VT are amenable to being cured by the creation of bundle or fascicular block. The mechanism of focal Purkinje VT is abnormal automaticity from the distal Purkinje system, and the ablation target is the earliest Purkinje activation during the VT. It is difficult to distinguish verapamil-sensitive fascicular VT from focal Purkinje VT by the 12-lead electrocardiogram; however, focal Purkinje VT is not responsive to verapamil . The recognition of the heterogeneity of these VTs and their unique characteristics should facilitate an appropriate diagnosis and therapy. 相似文献
10.
目的探讨三磷酸腺苷结合转运蛋白G家族成员2(ATP-binding cassette superfamily G member 2,ABCG2)抑制剂维拉帕米对体内外胰腺癌SW1990细胞侵袭转移能力影响及其机制。方法以终浓度分别为0、12.5、25、50、100和200μmol/L维拉帕米处理SW1990细胞24、48和72h后,以CCK-8法检测维拉帕米对SW1990细胞增殖抑制影响;RT-PCR和蛋白质印迹法检测维拉帕米对体内外SW1990细胞ABCG2mRNA及蛋白表达水平的影响;Transwell小室侵袭迁移实验及划痕实验分析维拉帕米处理后细胞侵袭迁移能力的改变。将SW1990细胞接种至裸鼠皮下,对比观察维拉帕米干扰前后肿瘤细胞在裸鼠体内的成瘤情况;免疫组化分析裸鼠肿瘤组织中ABCG2的表达。结果 CCK-8检测结果显示,浓度为25~100μmol/L维拉帕米对胰腺癌SW1990细胞的抑制呈现明显的剂量及时间依赖性。划痕实验结果显示,细胞平均迁移率比较,划痕24h维拉帕米组为(19.2±2.04)%,对照组为(36.8±2.25)%,t=-17.23,P<0.001;48h维拉帕米组为(43.7±3.14)%,对照组为(78.4±2.67)%,t=-23.85,P<0.001。Transwell侵袭实验结果显示,维拉帕米组平均穿膜细胞数为46.6±3.3,明显少于对照组的90.2±2.7,t=-47.2,P<0.001;迁移实验结果显示,维拉帕米组平均穿膜细胞数为61.4±2.8,亦少于对照组的110.3±3.5,t=-39.5,P<0.001;蛋白质印迹法及RT-PCR结果显示,维拉帕米能够明显降低体内外SW1990细胞ABCG2蛋白及mRNA的表达水平。裸鼠成瘤实验结果显示,细胞接种后10d左右可见肿瘤结节,50d时维拉帕米组裸鼠肿瘤体积为(521.6±48.5)mm3,小于对照组的(1 496.6±73.1)mm3,t=-38.6,P<0.001;维拉帕米组瘤质量(0.53±0.18)g,明显低于对照组(1.61±0.45)g,t=-22.49,P<0.001。免疫组化结果显示,维拉帕米能明显降低SW1990细胞ABCG2的表达。结论维拉帕米能明显抑制胰腺癌SW1990细胞在体内外的侵袭和转移,其机制可能与维拉帕米下调ABCG2的表达有关。 相似文献