In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation...In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.展开更多
Background: Increased brain P-glycoprotein (P-gp) expression may play important role in resistance to antiseizure drugs. The present work aimed to overcome the drug resistance that develop due to overexpression of P-g...Background: Increased brain P-glycoprotein (P-gp) expression may play important role in resistance to antiseizure drugs. The present work aimed to overcome the drug resistance that develop due to overexpression of P-gp with subsequent increase in brain phenytoin level in epileptic rats, using either non-selective (indomethacin) or selective (celecoxib) cyclooxygenase inhibitors. Methods: Fifty-six adult male albino rats were randomly divided into seven groups. Epilepsy was induced using the lithium pilocarpine model. Rats received indomethacin (2.5 mg/kg) or celecoxib (20 mg/kg), either alone or combined with phenytoin (50 mg/kg). Seizures were evaluated using Racine score. Motor coordination was assessed using open field and rotarod tests. Phenytoin brain level was measured using High Performance Liquid Chromatography (HPLC), glutamate expression was measured using Enzyme Linked Immunosorbent Assay (ELISA), ATP Binding Cassette Subfamily B Member 1 (ABCB1) gene expression was assessed using Real Time-Polymerase Chain Reaction (RT-PCR), and immunohistochemical analysis was done for P-gp expression. Results: Phenytoin combination with either indomethacin or celecoxib had improved the Racine score, motor coordination on rotarod apparatus, and open field test results. Also, phenytoin combination with either indomethacin or celecoxib decreased brain glutamate level, ABCB1 gene and P-gp expression, and increased brain phenytoin level compared to treatment with phenytoin alone. This indicated that both P-gp inhibitors indomethacin and celecoxib, increased the level of phenytoin that reached the brain of rats. However, brain uptake of phenytoin was significantly enhanced using celecoxib rather than indomethacin (CI 95%, 17.092: 32.808, P-value Conclusion: Cyclooxygenase inhibition using either celecoxib or indomethacin resulted in downregulation of P-gp expression, with subsequent increase in brain phenytoin level in epileptic rats.展开更多
介绍了一个新的基于优化推导出的核偏最小二乘(kernel partial least squares,K-PLS)的算法原理和实现步骤,并且给出了利用K-PLS法构建P-糖蛋白(P-glycoprotein,P-gp)黄酮类抑制剂的定量构效关系(QSAR)模型.利用该方法结合几个简单的分...介绍了一个新的基于优化推导出的核偏最小二乘(kernel partial least squares,K-PLS)的算法原理和实现步骤,并且给出了利用K-PLS法构建P-糖蛋白(P-glycoprotein,P-gp)黄酮类抑制剂的定量构效关系(QSAR)模型.利用该方法结合几个简单的分子拓扑参数,构建了具有高准确率的预测模型.该模型将有助于P-gp黄酮类抑制剂的虚拟筛选和理性设计.结果证明K-PLS是一个十分稳定可靠的方法,将会在化学计量学领域得到较好的应用和推广.展开更多
肿瘤多药耐药性(multiple drug resistance,MDR)的发生往往伴随着多药耐药基因如MDR1、MRP1和BCRP等高表达,其中MDR1基因编码的P-糖蛋白(P-glycoprotein,P-gp)是目前公认可以诱发癌细胞发生MDR的重要分子。传统研究认为P-gp主要是作为...肿瘤多药耐药性(multiple drug resistance,MDR)的发生往往伴随着多药耐药基因如MDR1、MRP1和BCRP等高表达,其中MDR1基因编码的P-糖蛋白(P-glycoprotein,P-gp)是目前公认可以诱发癌细胞发生MDR的重要分子。传统研究认为P-gp主要是作为一个药物泵将化疗药物从细胞内排出从而导致MDR。然而系列研究发现,除了介导MDR以外,P-gp还能够调节癌细胞的生长、增殖、凋亡、迁移和侵袭等其他生物学行为;而且研究表明P-gp的这些作用可以依赖,也可以不依赖于其药物泵的功能。这些结果表明P-gp能够通过一些新的机制促进肿瘤的进展。本文主要针对P-gp在促进肿瘤进展中的作用进行综述。展开更多
INTRODUCTIONMost advanced hepatocellular garcinoma (HCC) isinsensitive to most anticancer drugs which might berelated to the high frequency of expression of themultidrug resistance-1(MDR1) gene and itsproduct,P-glycop...INTRODUCTIONMost advanced hepatocellular garcinoma (HCC) isinsensitive to most anticancer drugs which might berelated to the high frequency of expression of themultidrug resistance-1(MDR1) gene and itsproduct,P-glycoprotein (p-gp).p-gp expressionmay also be concerned with tumor progression anddifferentiation.In the present study。展开更多
BACKGROUND:Multidrug resistance(MDR)is extremely common in hepatocellular carcinoma(HCC)and is a major problem in cancer eradication by limiting the efficacy of chemotherapy.Modulation of c-Jun NH2-terminal kinase(JNK...BACKGROUND:Multidrug resistance(MDR)is extremely common in hepatocellular carcinoma(HCC)and is a major problem in cancer eradication by limiting the efficacy of chemotherapy.Modulation of c-Jun NH2-terminal kinase(JNK)activation could be a new method to reverse MDR.However,the relationship between JNK activity and MDR in HCC cells is unknown.This study aimed to explore the relationship between MDR and JNK in HCC cell lines with different degrees of MDR.METHODS:A MDR human HCC cell line,SMMC-7721/ ADM,was developed by exposing parental cells to gradually increasing concentrations of adriamycin.The MTT assay was used to determine drug sensitivity.Flow cytometry was used to analyze the cell cycle distribution and to measure the expression levels of P-glycoprotein(P-gp)and MDR-related protein(MRP)-1 in these cells.JNK1,JNK2 and JNK3 mRNA expression levels were quantified by real-time PCR.Expression and phosphorylation of JNK1,JNK2,and JNK3 were analyzed by Western blotting.RESULTS:The MDR of SMMC-7721/ADM cells resistant to 0.05 mg/L adriamycin was mainly attributed to the overexpression of P-gp but not MRP1.In addition,these cells had a significant increase in percentage in the S phase,accompanied by a decrease in percentage in the G0/G1 phase,which is likely associated with a reduced ability for cell proliferation and MDR generation.We found that JNK1,JNK2,and JNK3 activities were negatively correlated with the degree of MDR in HCC cells.CONCLUSION:This study suggests that JNK1,JNK2,and JNK3 activities are negatively correlated with the degree of MDR in HCC cells.展开更多
Wutou-Gancao herb-pair is extensively used to attenuate the toxicity and enhance the efficacy of aconite.In this study,potential synergic mechanism of the herb pair was investigated by utilizing multiple ap-proaches.I...Wutou-Gancao herb-pair is extensively used to attenuate the toxicity and enhance the efficacy of aconite.In this study,potential synergic mechanism of the herb pair was investigated by utilizing multiple ap-proaches.In silico and in vitro Caco-2 cell models were applied to study the potential binding mode of bioactive ingredients existing in liquorice with P-glycoprotein(P-gp),as well as the inhibition effects on P-gp.Additionally,anti-inflammatory activity of aconitine(AC)combined with active ingredients of liquorice,as well as pharmacokinetic patterns of AC after co-administration was investigated.Anti-inflammatory effect of AC(1 mg/kg)in rats was enhanced in combination with bioactive ingredients of liquorice(10 mg/kg).In the meanwhile,the exposure of AC in vivo was altered,in terms of Cmax and AUC.For instance,the Cmax and AUC were increased to 1.9 and 1.3 folds,respectively,when used in combination with liquiritigenin.The in silico study revealed the potential binding mode with outward facing conformation of P-gp.The resulting data obtained from transport of rhodamine-123(Rh-123)across Caco-2 cell monolayer further indicated that the function of P-gp was inhibited by chemicals in liquorice.The synergic effect was therefore proposed to be attributed to inhibition of P-gp by liquorice since AC has been demonstrated to be the substrate of P-gp.The resuls revealed that potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting function of key efflux transporter P-gp to enhance the exposure of AC in systematic circulation,and further the anti-inflammatory effect,which helps clarify the compatibility rationale of these two herbs.展开更多
The main purpose of treatment of rheumatoid arthritis(RA) with disease modifying antirheumatic drugs(DMARDs) is to control activation of lymphocytes,although some patients do not respond adequately to such treatment. ...The main purpose of treatment of rheumatoid arthritis(RA) with disease modifying antirheumatic drugs(DMARDs) is to control activation of lymphocytes,although some patients do not respond adequately to such treatment. Among various mechanisms of multidrug resistance, P-glycoprotein(P-gp), a member of ATP-binding cassette transporters, causes drugresistance by efflux of intracellular drugs. Certain stimuli,such as tumor necrosis factor-α, activate lymphocytes and induce P-gp expression on lymphocytes, as evident in active RA. Studies from our laboratories showed spontaneous nuclear accumulation of human Y-boxbinding protein-1, a multidrug resistance 1 transcription factor, in unstimulated lymphocytes, and surface overexpression of P-gp on peripheral lymphocytes of RA patients with high disease activity. The significant correlation between P-gp expression level and RA disease activity is associated with active efflux of drugs from the lymphocyte cytoplasm and in drugresistance.However, the use of biological agents that reduce P-gp expression as well as P-gp antagonists(e.g., cyclosporine) can successfully reduce the efflux of corticosteroids from lymphocytes in vitro, suggesting that both types of drugs can be used to overcome drug-resistance and improve clinical outcome. We conclude that lymphocytes activated by various stimuli in RA patients with highly active disease acquire P-gpmediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. Expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable therapeutic target to prevent drug resistance in patients with active RA.展开更多
The intestinal uptake of paclitaxel is hampered by trans-membrane efflux transporters such as P-glycoprotein(P-gp),and paclitaxel is mainly metabolized by cytochrome P4503A4(CYP3A4)presented in the liver.Our previous ...The intestinal uptake of paclitaxel is hampered by trans-membrane efflux transporters such as P-glycoprotein(P-gp),and paclitaxel is mainly metabolized by cytochrome P4503A4(CYP3A4)presented in the liver.Our previous results demonstrated that flavonoids extracted from Taxus yunnanensis could improve the oral absorption of paclitaxel.The current study was purposed to investigate the effects of the flavonoid extracts on P-gp and CYP3A4 in vitro.The expression and activity of P-gp were detected by western blotting and intracellular rhodamine 123 accumulation assay in Caco-2 cells treated with the flavonoids extract.The expression of CYP3A4 was investigated by western blotting in mouse primary hepatocytes and the activity of CYP3A4 was detected by LC-MS/MS method using rat liver microsomes.Our results showed that the flavonoid extracts from T.yunnanensis could inhibit P-gp activity and concurrently decrease the expression and activity of CYP3A4.In conclusion,activity of P-gp and CYP3A4 could be inhibited by flavonoids extracted from T.yunnanensis which might be potential candidates for development of oral formulation of paclitaxel.展开更多
Epileptic seizures induce overexpression of P-glycoprotein in the blood-brain barrier. However, it is unclear whether hippocampal neurons also overexpress P-glycoprotein following seizure. This study confirmed that th...Epileptic seizures induce overexpression of P-glycoprotein in the blood-brain barrier. However, it is unclear whether hippocampal neurons also overexpress P-glycoprotein following seizure. This study confirmed that the clinical manifestation, pathological characteristics and electroencephalography in the rat model of lithium-pilocarpine-induced mesial temporal lobe epilepsy were consistent with clinical reports of mesial temporal lobe epilepsy in humans.Immunohistochemistry staining demonstrated that P-glycoprotein positive staining was found in neurons in the pyramidal layer of the hippocampus. Westem blot assay and real-time polymerase chain reaction revealed that P-glycoprotein overexpression was exhibited in the CA1, CA3, and dentate gyrus of the hippocampus at 24 and 60 days following model induction, but no significant dffierence was detected in the same region at various time points. These results indicate that seizures led to overexpression of P-glycoprotein in neurons of the hippocampus, but no evidence was found for a positive association between P-glycoprotein expression and seizure frequency.展开更多
AIM: To investigate the role of oxidative stress in regulating the functional expression of P-glycoprotein(P-gp) in mitochondria of D407 cells.METHODS: D407 cells were exposed to different ranges of concentrations...AIM: To investigate the role of oxidative stress in regulating the functional expression of P-glycoprotein(P-gp) in mitochondria of D407 cells.METHODS: D407 cells were exposed to different ranges of concentrations of H2O2. The mitochondrial location of P-gp in the cells subjected to oxidative stress was detected by confocal analysis. Expression of P-gp in isolated mitochondria was assessed by Western blot. The pump activity of P-gp was evaluated by performing the efflux study on isolated mitochondria with Rhodamine 123(Rho-123) alone and in the presence of P-gp inhibitor(Tariquidar) using flow cytometry analysis. The cells were pretreated with 10 mmol/L N-acetylcysteine(NAC) for 30 min before exposing to H2O2, and analyzed the mitochondrial extracts by Western blot and flow cytometry.RESULTS: P-gp was co-localized in the mitochondria by confocal laser scanning microscopy, and it was also detected in the mitochondria of D407 cells using Western blot. Exposure to increasing concentrations of H2O2 led to gradually increased expression and location of P-gp in the mitochondria of cells. Rho-123 efflux assay showed higher uptake of Rho-123 on isolated mitochondria in the presence of Tariquidar both in normal and oxidative stress state. H2O2 up-regulated P-gp in D407 cells, which could be reversed by NAC treatment. CONCLUSION: H2O2 could up-regulate the functional expression of P-gp in mitochondria of D407 cells, while antioxidants might suppress oxidative-stress-induced over-expression of functional P-gp. It is indicative that limiting the mitochondrial P-gp transport in retinal pigment epithelium cells would be to improve the effect of mitochondria-targeted antioxidant therapy in age-related macular degeneration-like retinopathy.展开更多
Objective: To investigate the expression of MDR-1 P-glycoprotein(MDR-1 Pgp) in breast cancer and analyze its correlation to the biological behavior and prognosis of the disease. Methods:The expression of MDR-1 Pgp...Objective: To investigate the expression of MDR-1 P-glycoprotein(MDR-1 Pgp) in breast cancer and analyze its correlation to the biological behavior and prognosis of the disease. Methods:The expression of MDR-1 Pgp was examined in 75 cases of breast cancer patients by using three different monoclonal antibodies(JSB1, C219 and C494) with S-P immunohistochemisty. These patients were followed up for 5 years, and the correlation between MDR-1 Pgp expression, survival rate and lymph metastasis was analyzed. Results: Positive detection of MDR-1 Pgp by JSB1, C219 and C494 in 75 cases of breast cancer was 86.7%, 48% and 85.3%, respectively. MDR-1 Pgp expression was not related to ages of patients (P 〉 0.05). JSBl-detected expression of MDR-1 Pgp was related to lymph node metastasis(P〈 0.05); while C219 and C494 were not(P 〉 0.05). The patients with MDR-1 Pgp expression positively detected by either two of the three antibodies, had five-year survival rate that was significantly higher than those positively detected by all the three antibodies(P 〈 0.05). Conclusion:Three antibodies should be used simultaneously to detect MDR-1 Pgp expression in breast cancer. Positive MDR-1 Pgp expression in breast cancer detected by all the three antibodies may represent a poor prognosis; while positive MDR-1 Pgp detection by JSB1 and C494 is associated with lymph metastasis.展开更多
Over-expression of P-glycoprotein(P-gp),an ATP-dependent drug efflux pump,represents one of the major mechanisms that contribute to multidrug resistance(MDR) in cancer cells.This study examined the effects of troglita...Over-expression of P-glycoprotein(P-gp),an ATP-dependent drug efflux pump,represents one of the major mechanisms that contribute to multidrug resistance(MDR) in cancer cells.This study examined the effects of troglitazone,a ligand of peroxisome proliferator-activated receptor gamma(PPARγ),on P-gp-mediated MDR in SGC7901/VCR cells(a vincristine-resistant human gastric cancer cell line).The expression of P-gp was detected by RT-PCR and Western blotting,respectively.The SGC7901/VCR cells were treated with 0.1 mg/L vincristine(VCR) alone or in combination with 1,5,10 μmol/L troglitazone for 24 h.PPARγ was measured by electrophoretic mobility shift assay(EMSA).The intracellular concentration of Rhodamine123(Rh123,a fluorescent P-gp substrate) was assayed to evaluate the activity of P-gp.The cell cycle and apoptosis were measured by flow cytometry.The results showed that the P-gp was increasingly expressed in SGC7901,BGC823 and SGC7901/VCR cells in turn,suggesting that MDR in the SGC7901/VCR cells was mediated by the increased expression of P-gp.In the SGC7901/VCR cells,the expression level of total PPARγ was increased,however,the protein level and activity of PPARγ in the nuclei of cells decreased significantly.Troglitazone elevated the PPARγ activity in SGC7901/VCR cells in a dose-dependent manner.Troglitazone decreased the P-gp expression and markedly enhanced the accumulation of Rh123 in SGC7901/VCR cells in a dose-dependent manner.We also found that troglitazone significantly increased the percentage of SGC7901/VCR cells in the G2/M phase and decreased the cell percentage in G1 and S phase in a dose-dependent manner.Troglitazone significantly increased the apoptotic rate of SGC7901/VCR cells treated by VCR or ADR in a dose-dependent manner.It was concluded that P-gp-overexpressed SGC7901/VCR cells have minor endogenous PPARγ activity.Elevation of the PPARγ activity by troglitazone can reverse P-gp-mediated MDR via down-regulating the expression and activity of P-gp in SGC7901/VCR cells.It was suggested that troglitazone can dramatically enhance the sensitivity of P-gp-mediated MDR cancer cells to chemotherapeutic agents.展开更多
Objective: To investigate the regulation of p-glycoprotein (PgP) and GST expression from three reversors in ADM-sensitive and ADM-resistant human leukemic cell lines and KB cell lines. Methods: Immunocytochemical(ICC)...Objective: To investigate the regulation of p-glycoprotein (PgP) and GST expression from three reversors in ADM-sensitive and ADM-resistant human leukemic cell lines and KB cell lines. Methods: Immunocytochemical(ICC) technique was applied to detect the multidrug-resistant gene products, PgP and GST in K562 cells, K562/ADM cells and KB cells before or after treatment with three resistant reversors, i.e., verapamil(VER), dipyriamole(DPM) and cyclosporin A(CsA). Results: PgP expression was observed in K562/ADM cells but not in K562 cells or KB cells, and GSTPI expression, in KB cells but not in K562 cells or K562/ADM cells. Overexpressions of PgP were induced after treatment with VER, or DPM or CsA for 24 h in K562 cells but not KB cells. DPM-treated K562/ADM cells expressed PgP much lower than DPM-ree of K562/ADM cells with CsA for 24 h. Induced GSTPI expression was found after treatment with DPM, but not VER or CsA in K562 cells. No significant difference was observed for GSTPI expresion in KB cells before and after treatment with VER, or DPM, or CsA. Conclusion: The findings suggested that reversal activity of some drug resistant reversors, such as VER, DPM, CsA, may be declined by themselves through induction of PgP, perhaps GST.展开更多
Objective: to study the clinical significance of P-glycoprotein (P-gp) in breast cancer. Methods: Expression of P-gp in 60 cases of breast cancer was examined by immunohistochemistry. P-gp expression and response to c...Objective: to study the clinical significance of P-glycoprotein (P-gp) in breast cancer. Methods: Expression of P-gp in 60 cases of breast cancer was examined by immunohistochemistry. P-gp expression and response to chemotherapy were comparatively investigated in 19 patients with metastatic breast cancer. Results: The P-gp was positive in 48.3% of the 60 cases of breast cancer. P-gp expression was not related to patients' age, menstruation status, number of axillary lymph nodes involved, clinical stage, histological type, and hormonal receptor status (P>0.05). The frequency of metastasis (62.1%) and mortality (51.7%) were higher in P-gp positive cases than in negative cases (16.1% vs 12.9%, P<0.005). The 5-year survival rate of P-gp positive cases (48.3%) was significantly lower than that of negative cases (87.1%) (P<0.05). In patients who received adjuvant chemotherapy distant metastasis occurred more frequently in the P-gp positive cases (94.7%) than in the P-gp negative cases (57.1%) (P=0.0468). More P-gp negative patients (7/9) than positive patients (1/10) were responsive to chemotherapy (P=0.0055). Conclusion: Immunohistochemical examination of P-gp expression is useful in predicting response to chemotherapy and prognosis in breast cancer patients. P-gp positivity is associated with poor prognosis.展开更多
Objectives: To evaluate the expression of P-glycoprotein (P-gp) and it's effect on chemotherapy response in metastatic breast carcinoma. Methods: 46 postoperative patients with metastatic breast carcinoma were enr...Objectives: To evaluate the expression of P-glycoprotein (P-gp) and it's effect on chemotherapy response in metastatic breast carcinoma. Methods: 46 postoperative patients with metastatic breast carcinoma were enrolled. P-gp expression was detected by SABC immunohistochemical method. These patients were treated with combined chemotherapy of cyclophosphamide, pirarubicin and 5-fluorouracil for at least two cycles. The relationship between P-gp expression and chemotherapeutic response was analyzed. Results: The positive rate of P-gp expression was 56.5%, the P-gp expression in the patients with lung or liver metastasis was higher than that in patients with skin or lymph node metastasis (P=0.049). The overall response rate was 58.1% in 43 patients; the response rate (89.5%) of the P-gp negative group was higher than that (30.0%) of the P-gp positive group (P<0.01). The response rate (87.5%) in the patients with skin or lymph node metastasis was higher than that (40.7%) in the patients with lung or liver metastasis (P<0.05). In the postoperative patients who had received CAF or CMF regimen adjuvant chemotherapy previously, the response rate of metastatic diseases to chemotherapy had no significant difference (71.4% and 37.5%, respectively) (P=0.052). Conclusion: Patients with metastatic breast carcinoma had higher P-gp expression and these patients should be treated with non-MDR drugs chemotherapy.展开更多
Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate ba...Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate back into the systemic circulation.The aim of the present study was to develop an intravenous formulation of HM30181 A(HM)to inhibit P-gp in the brain to effectively deliver paclitaxel(PTX)for the treatment of malignant glioma.Methods:Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies:i)spray-drying[polyvinlypyrrolidone(PVP)-HM]and ii)solvent evaporation[HP-β-cyclodextrin(cyclodextrin)-HM].The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells.Blood and brain pharmacokinetic parameters were also determined,and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model.Results:Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro,cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM.Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg,and the mice began to lose weight at doses above this level.Cyclodextrin-HM(10 mg/kg)administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model,according to both tumor volume measurement and survival time(P<0.05).Conclusions:In a mouse orthotopic brain tumor model,the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.展开更多
基金supported by the National Key Research and Development Program of ChinaNos.2021YFC2 701800 and 2021YFC2 701805 (to QY)+2 种基金Open Research Fund of State Key Laboratory of Genetic EngineeringFudan UniversityNo.SKLGE-21 19 (to TXH and QY)
文摘In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.
文摘Background: Increased brain P-glycoprotein (P-gp) expression may play important role in resistance to antiseizure drugs. The present work aimed to overcome the drug resistance that develop due to overexpression of P-gp with subsequent increase in brain phenytoin level in epileptic rats, using either non-selective (indomethacin) or selective (celecoxib) cyclooxygenase inhibitors. Methods: Fifty-six adult male albino rats were randomly divided into seven groups. Epilepsy was induced using the lithium pilocarpine model. Rats received indomethacin (2.5 mg/kg) or celecoxib (20 mg/kg), either alone or combined with phenytoin (50 mg/kg). Seizures were evaluated using Racine score. Motor coordination was assessed using open field and rotarod tests. Phenytoin brain level was measured using High Performance Liquid Chromatography (HPLC), glutamate expression was measured using Enzyme Linked Immunosorbent Assay (ELISA), ATP Binding Cassette Subfamily B Member 1 (ABCB1) gene expression was assessed using Real Time-Polymerase Chain Reaction (RT-PCR), and immunohistochemical analysis was done for P-gp expression. Results: Phenytoin combination with either indomethacin or celecoxib had improved the Racine score, motor coordination on rotarod apparatus, and open field test results. Also, phenytoin combination with either indomethacin or celecoxib decreased brain glutamate level, ABCB1 gene and P-gp expression, and increased brain phenytoin level compared to treatment with phenytoin alone. This indicated that both P-gp inhibitors indomethacin and celecoxib, increased the level of phenytoin that reached the brain of rats. However, brain uptake of phenytoin was significantly enhanced using celecoxib rather than indomethacin (CI 95%, 17.092: 32.808, P-value Conclusion: Cyclooxygenase inhibition using either celecoxib or indomethacin resulted in downregulation of P-gp expression, with subsequent increase in brain phenytoin level in epileptic rats.
文摘介绍了一个新的基于优化推导出的核偏最小二乘(kernel partial least squares,K-PLS)的算法原理和实现步骤,并且给出了利用K-PLS法构建P-糖蛋白(P-glycoprotein,P-gp)黄酮类抑制剂的定量构效关系(QSAR)模型.利用该方法结合几个简单的分子拓扑参数,构建了具有高准确率的预测模型.该模型将有助于P-gp黄酮类抑制剂的虚拟筛选和理性设计.结果证明K-PLS是一个十分稳定可靠的方法,将会在化学计量学领域得到较好的应用和推广.
文摘肿瘤多药耐药性(multiple drug resistance,MDR)的发生往往伴随着多药耐药基因如MDR1、MRP1和BCRP等高表达,其中MDR1基因编码的P-糖蛋白(P-glycoprotein,P-gp)是目前公认可以诱发癌细胞发生MDR的重要分子。传统研究认为P-gp主要是作为一个药物泵将化疗药物从细胞内排出从而导致MDR。然而系列研究发现,除了介导MDR以外,P-gp还能够调节癌细胞的生长、增殖、凋亡、迁移和侵袭等其他生物学行为;而且研究表明P-gp的这些作用可以依赖,也可以不依赖于其药物泵的功能。这些结果表明P-gp能够通过一些新的机制促进肿瘤的进展。本文主要针对P-gp在促进肿瘤进展中的作用进行综述。
基金the China Medical Board of New York,Inc.,USA,Grant No.90-534
文摘INTRODUCTIONMost advanced hepatocellular garcinoma (HCC) isinsensitive to most anticancer drugs which might berelated to the high frequency of expression of themultidrug resistance-1(MDR1) gene and itsproduct,P-glycoprotein (p-gp).p-gp expressionmay also be concerned with tumor progression anddifferentiation.In the present study。
基金supported by grants from the Medical Innovation Fundation of Fujian Province(No.2007-CXB-7)the Natural Science Foundation of Fujian Province(No.2009D010)
文摘BACKGROUND:Multidrug resistance(MDR)is extremely common in hepatocellular carcinoma(HCC)and is a major problem in cancer eradication by limiting the efficacy of chemotherapy.Modulation of c-Jun NH2-terminal kinase(JNK)activation could be a new method to reverse MDR.However,the relationship between JNK activity and MDR in HCC cells is unknown.This study aimed to explore the relationship between MDR and JNK in HCC cell lines with different degrees of MDR.METHODS:A MDR human HCC cell line,SMMC-7721/ ADM,was developed by exposing parental cells to gradually increasing concentrations of adriamycin.The MTT assay was used to determine drug sensitivity.Flow cytometry was used to analyze the cell cycle distribution and to measure the expression levels of P-glycoprotein(P-gp)and MDR-related protein(MRP)-1 in these cells.JNK1,JNK2 and JNK3 mRNA expression levels were quantified by real-time PCR.Expression and phosphorylation of JNK1,JNK2,and JNK3 were analyzed by Western blotting.RESULTS:The MDR of SMMC-7721/ADM cells resistant to 0.05 mg/L adriamycin was mainly attributed to the overexpression of P-gp but not MRP1.In addition,these cells had a significant increase in percentage in the S phase,accompanied by a decrease in percentage in the G0/G1 phase,which is likely associated with a reduced ability for cell proliferation and MDR generation.We found that JNK1,JNK2,and JNK3 activities were negatively correlated with the degree of MDR in HCC cells.CONCLUSION:This study suggests that JNK1,JNK2,and JNK3 activities are negatively correlated with the degree of MDR in HCC cells.
基金supported by National Key Research and Development Program(Grant2016YFE0121400)National Natural Science Foundation of China(Grant No.81430096)+2 种基金Macao Science and Technology Development Fund(006/2015/AMJ to Y.Xie)the program of Changjiang Scholars and innovative Research Team in University(No.IRT_14R41)Tianjin Natural and Science Foundation(No.17YFZCSY01170)。
文摘Wutou-Gancao herb-pair is extensively used to attenuate the toxicity and enhance the efficacy of aconite.In this study,potential synergic mechanism of the herb pair was investigated by utilizing multiple ap-proaches.In silico and in vitro Caco-2 cell models were applied to study the potential binding mode of bioactive ingredients existing in liquorice with P-glycoprotein(P-gp),as well as the inhibition effects on P-gp.Additionally,anti-inflammatory activity of aconitine(AC)combined with active ingredients of liquorice,as well as pharmacokinetic patterns of AC after co-administration was investigated.Anti-inflammatory effect of AC(1 mg/kg)in rats was enhanced in combination with bioactive ingredients of liquorice(10 mg/kg).In the meanwhile,the exposure of AC in vivo was altered,in terms of Cmax and AUC.For instance,the Cmax and AUC were increased to 1.9 and 1.3 folds,respectively,when used in combination with liquiritigenin.The in silico study revealed the potential binding mode with outward facing conformation of P-gp.The resulting data obtained from transport of rhodamine-123(Rh-123)across Caco-2 cell monolayer further indicated that the function of P-gp was inhibited by chemicals in liquorice.The synergic effect was therefore proposed to be attributed to inhibition of P-gp by liquorice since AC has been demonstrated to be the substrate of P-gp.The resuls revealed that potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting function of key efflux transporter P-gp to enhance the exposure of AC in systematic circulation,and further the anti-inflammatory effect,which helps clarify the compatibility rationale of these two herbs.
基金Supported by In part by research Grants-In-Aid for Scientific Research by the Ministry of Health,Labor and Welfare of Japanthe Ministry of Education,Culture,Sports,Science and Technology of JapanUniversity of Occupational and Environmental Health,Japan
文摘The main purpose of treatment of rheumatoid arthritis(RA) with disease modifying antirheumatic drugs(DMARDs) is to control activation of lymphocytes,although some patients do not respond adequately to such treatment. Among various mechanisms of multidrug resistance, P-glycoprotein(P-gp), a member of ATP-binding cassette transporters, causes drugresistance by efflux of intracellular drugs. Certain stimuli,such as tumor necrosis factor-α, activate lymphocytes and induce P-gp expression on lymphocytes, as evident in active RA. Studies from our laboratories showed spontaneous nuclear accumulation of human Y-boxbinding protein-1, a multidrug resistance 1 transcription factor, in unstimulated lymphocytes, and surface overexpression of P-gp on peripheral lymphocytes of RA patients with high disease activity. The significant correlation between P-gp expression level and RA disease activity is associated with active efflux of drugs from the lymphocyte cytoplasm and in drugresistance.However, the use of biological agents that reduce P-gp expression as well as P-gp antagonists(e.g., cyclosporine) can successfully reduce the efflux of corticosteroids from lymphocytes in vitro, suggesting that both types of drugs can be used to overcome drug-resistance and improve clinical outcome. We conclude that lymphocytes activated by various stimuli in RA patients with highly active disease acquire P-gpmediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. Expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable therapeutic target to prevent drug resistance in patients with active RA.
基金The work was supported by Foundation from Guangdong Province Science and Technology Department(Grant number:2012A080202013 and 2009A030100002)National Natural Science Foundations of China(Grant number:81202961)the National Major Projects for science and technology development from Science and Technology Ministry of China(Grant No.2012ZX09506001-004).
文摘The intestinal uptake of paclitaxel is hampered by trans-membrane efflux transporters such as P-glycoprotein(P-gp),and paclitaxel is mainly metabolized by cytochrome P4503A4(CYP3A4)presented in the liver.Our previous results demonstrated that flavonoids extracted from Taxus yunnanensis could improve the oral absorption of paclitaxel.The current study was purposed to investigate the effects of the flavonoid extracts on P-gp and CYP3A4 in vitro.The expression and activity of P-gp were detected by western blotting and intracellular rhodamine 123 accumulation assay in Caco-2 cells treated with the flavonoids extract.The expression of CYP3A4 was investigated by western blotting in mouse primary hepatocytes and the activity of CYP3A4 was detected by LC-MS/MS method using rat liver microsomes.Our results showed that the flavonoid extracts from T.yunnanensis could inhibit P-gp activity and concurrently decrease the expression and activity of CYP3A4.In conclusion,activity of P-gp and CYP3A4 could be inhibited by flavonoids extracted from T.yunnanensis which might be potential candidates for development of oral formulation of paclitaxel.
基金the Science and Technology Foundation of Guangdong Province,No.2009B060700049,2008B060600063the National Natural Science Foundation of China,No.10671213
文摘Epileptic seizures induce overexpression of P-glycoprotein in the blood-brain barrier. However, it is unclear whether hippocampal neurons also overexpress P-glycoprotein following seizure. This study confirmed that the clinical manifestation, pathological characteristics and electroencephalography in the rat model of lithium-pilocarpine-induced mesial temporal lobe epilepsy were consistent with clinical reports of mesial temporal lobe epilepsy in humans.Immunohistochemistry staining demonstrated that P-glycoprotein positive staining was found in neurons in the pyramidal layer of the hippocampus. Westem blot assay and real-time polymerase chain reaction revealed that P-glycoprotein overexpression was exhibited in the CA1, CA3, and dentate gyrus of the hippocampus at 24 and 60 days following model induction, but no significant dffierence was detected in the same region at various time points. These results indicate that seizures led to overexpression of P-glycoprotein in neurons of the hippocampus, but no evidence was found for a positive association between P-glycoprotein expression and seizure frequency.
基金Supported by National Natural Science Foundation of China(No.81400424)Guangdong Medical Science Foundation(No.A2015151)
文摘AIM: To investigate the role of oxidative stress in regulating the functional expression of P-glycoprotein(P-gp) in mitochondria of D407 cells.METHODS: D407 cells were exposed to different ranges of concentrations of H2O2. The mitochondrial location of P-gp in the cells subjected to oxidative stress was detected by confocal analysis. Expression of P-gp in isolated mitochondria was assessed by Western blot. The pump activity of P-gp was evaluated by performing the efflux study on isolated mitochondria with Rhodamine 123(Rho-123) alone and in the presence of P-gp inhibitor(Tariquidar) using flow cytometry analysis. The cells were pretreated with 10 mmol/L N-acetylcysteine(NAC) for 30 min before exposing to H2O2, and analyzed the mitochondrial extracts by Western blot and flow cytometry.RESULTS: P-gp was co-localized in the mitochondria by confocal laser scanning microscopy, and it was also detected in the mitochondria of D407 cells using Western blot. Exposure to increasing concentrations of H2O2 led to gradually increased expression and location of P-gp in the mitochondria of cells. Rho-123 efflux assay showed higher uptake of Rho-123 on isolated mitochondria in the presence of Tariquidar both in normal and oxidative stress state. H2O2 up-regulated P-gp in D407 cells, which could be reversed by NAC treatment. CONCLUSION: H2O2 could up-regulate the functional expression of P-gp in mitochondria of D407 cells, while antioxidants might suppress oxidative-stress-induced over-expression of functional P-gp. It is indicative that limiting the mitochondrial P-gp transport in retinal pigment epithelium cells would be to improve the effect of mitochondria-targeted antioxidant therapy in age-related macular degeneration-like retinopathy.
基金This work was supported by the Science Development Foundation of the Nanjing Medical University(2006NMUZ023)The research in Dr. W. Zhang's laboratory was supported by funding from the National Research Council of Canada and a Canadian Research Program spon- sored by CIHR, HSFC, ASC and Pfizer(PG-04-0248)
文摘Objective: To investigate the expression of MDR-1 P-glycoprotein(MDR-1 Pgp) in breast cancer and analyze its correlation to the biological behavior and prognosis of the disease. Methods:The expression of MDR-1 Pgp was examined in 75 cases of breast cancer patients by using three different monoclonal antibodies(JSB1, C219 and C494) with S-P immunohistochemisty. These patients were followed up for 5 years, and the correlation between MDR-1 Pgp expression, survival rate and lymph metastasis was analyzed. Results: Positive detection of MDR-1 Pgp by JSB1, C219 and C494 in 75 cases of breast cancer was 86.7%, 48% and 85.3%, respectively. MDR-1 Pgp expression was not related to ages of patients (P 〉 0.05). JSBl-detected expression of MDR-1 Pgp was related to lymph node metastasis(P〈 0.05); while C219 and C494 were not(P 〉 0.05). The patients with MDR-1 Pgp expression positively detected by either two of the three antibodies, had five-year survival rate that was significantly higher than those positively detected by all the three antibodies(P 〈 0.05). Conclusion:Three antibodies should be used simultaneously to detect MDR-1 Pgp expression in breast cancer. Positive MDR-1 Pgp expression in breast cancer detected by all the three antibodies may represent a poor prognosis; while positive MDR-1 Pgp detection by JSB1 and C494 is associated with lymph metastasis.
基金supported by grants from Natural Sciences Foundation of Hubei Province (No.2007ABA065)Science and Technology Key Project of Health Bureau of Hubei Province (No.JX1B006)
文摘Over-expression of P-glycoprotein(P-gp),an ATP-dependent drug efflux pump,represents one of the major mechanisms that contribute to multidrug resistance(MDR) in cancer cells.This study examined the effects of troglitazone,a ligand of peroxisome proliferator-activated receptor gamma(PPARγ),on P-gp-mediated MDR in SGC7901/VCR cells(a vincristine-resistant human gastric cancer cell line).The expression of P-gp was detected by RT-PCR and Western blotting,respectively.The SGC7901/VCR cells were treated with 0.1 mg/L vincristine(VCR) alone or in combination with 1,5,10 μmol/L troglitazone for 24 h.PPARγ was measured by electrophoretic mobility shift assay(EMSA).The intracellular concentration of Rhodamine123(Rh123,a fluorescent P-gp substrate) was assayed to evaluate the activity of P-gp.The cell cycle and apoptosis were measured by flow cytometry.The results showed that the P-gp was increasingly expressed in SGC7901,BGC823 and SGC7901/VCR cells in turn,suggesting that MDR in the SGC7901/VCR cells was mediated by the increased expression of P-gp.In the SGC7901/VCR cells,the expression level of total PPARγ was increased,however,the protein level and activity of PPARγ in the nuclei of cells decreased significantly.Troglitazone elevated the PPARγ activity in SGC7901/VCR cells in a dose-dependent manner.Troglitazone decreased the P-gp expression and markedly enhanced the accumulation of Rh123 in SGC7901/VCR cells in a dose-dependent manner.We also found that troglitazone significantly increased the percentage of SGC7901/VCR cells in the G2/M phase and decreased the cell percentage in G1 and S phase in a dose-dependent manner.Troglitazone significantly increased the apoptotic rate of SGC7901/VCR cells treated by VCR or ADR in a dose-dependent manner.It was concluded that P-gp-overexpressed SGC7901/VCR cells have minor endogenous PPARγ activity.Elevation of the PPARγ activity by troglitazone can reverse P-gp-mediated MDR via down-regulating the expression and activity of P-gp in SGC7901/VCR cells.It was suggested that troglitazone can dramatically enhance the sensitivity of P-gp-mediated MDR cancer cells to chemotherapeutic agents.
文摘Objective: To investigate the regulation of p-glycoprotein (PgP) and GST expression from three reversors in ADM-sensitive and ADM-resistant human leukemic cell lines and KB cell lines. Methods: Immunocytochemical(ICC) technique was applied to detect the multidrug-resistant gene products, PgP and GST in K562 cells, K562/ADM cells and KB cells before or after treatment with three resistant reversors, i.e., verapamil(VER), dipyriamole(DPM) and cyclosporin A(CsA). Results: PgP expression was observed in K562/ADM cells but not in K562 cells or KB cells, and GSTPI expression, in KB cells but not in K562 cells or K562/ADM cells. Overexpressions of PgP were induced after treatment with VER, or DPM or CsA for 24 h in K562 cells but not KB cells. DPM-treated K562/ADM cells expressed PgP much lower than DPM-ree of K562/ADM cells with CsA for 24 h. Induced GSTPI expression was found after treatment with DPM, but not VER or CsA in K562 cells. No significant difference was observed for GSTPI expresion in KB cells before and after treatment with VER, or DPM, or CsA. Conclusion: The findings suggested that reversal activity of some drug resistant reversors, such as VER, DPM, CsA, may be declined by themselves through induction of PgP, perhaps GST.
文摘Objective: to study the clinical significance of P-glycoprotein (P-gp) in breast cancer. Methods: Expression of P-gp in 60 cases of breast cancer was examined by immunohistochemistry. P-gp expression and response to chemotherapy were comparatively investigated in 19 patients with metastatic breast cancer. Results: The P-gp was positive in 48.3% of the 60 cases of breast cancer. P-gp expression was not related to patients' age, menstruation status, number of axillary lymph nodes involved, clinical stage, histological type, and hormonal receptor status (P>0.05). The frequency of metastasis (62.1%) and mortality (51.7%) were higher in P-gp positive cases than in negative cases (16.1% vs 12.9%, P<0.005). The 5-year survival rate of P-gp positive cases (48.3%) was significantly lower than that of negative cases (87.1%) (P<0.05). In patients who received adjuvant chemotherapy distant metastasis occurred more frequently in the P-gp positive cases (94.7%) than in the P-gp negative cases (57.1%) (P=0.0468). More P-gp negative patients (7/9) than positive patients (1/10) were responsive to chemotherapy (P=0.0055). Conclusion: Immunohistochemical examination of P-gp expression is useful in predicting response to chemotherapy and prognosis in breast cancer patients. P-gp positivity is associated with poor prognosis.
文摘Objectives: To evaluate the expression of P-glycoprotein (P-gp) and it's effect on chemotherapy response in metastatic breast carcinoma. Methods: 46 postoperative patients with metastatic breast carcinoma were enrolled. P-gp expression was detected by SABC immunohistochemical method. These patients were treated with combined chemotherapy of cyclophosphamide, pirarubicin and 5-fluorouracil for at least two cycles. The relationship between P-gp expression and chemotherapeutic response was analyzed. Results: The positive rate of P-gp expression was 56.5%, the P-gp expression in the patients with lung or liver metastasis was higher than that in patients with skin or lymph node metastasis (P=0.049). The overall response rate was 58.1% in 43 patients; the response rate (89.5%) of the P-gp negative group was higher than that (30.0%) of the P-gp positive group (P<0.01). The response rate (87.5%) in the patients with skin or lymph node metastasis was higher than that (40.7%) in the patients with lung or liver metastasis (P<0.05). In the postoperative patients who had received CAF or CMF regimen adjuvant chemotherapy previously, the response rate of metastatic diseases to chemotherapy had no significant difference (71.4% and 37.5%, respectively) (P=0.052). Conclusion: Patients with metastatic breast carcinoma had higher P-gp expression and these patients should be treated with non-MDR drugs chemotherapy.
基金supported by a FDCT grant from the Macao Science and Technology Development Fund(Grant No.061/2014/A2)。
文摘Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate back into the systemic circulation.The aim of the present study was to develop an intravenous formulation of HM30181 A(HM)to inhibit P-gp in the brain to effectively deliver paclitaxel(PTX)for the treatment of malignant glioma.Methods:Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies:i)spray-drying[polyvinlypyrrolidone(PVP)-HM]and ii)solvent evaporation[HP-β-cyclodextrin(cyclodextrin)-HM].The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells.Blood and brain pharmacokinetic parameters were also determined,and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model.Results:Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro,cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM.Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg,and the mice began to lose weight at doses above this level.Cyclodextrin-HM(10 mg/kg)administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model,according to both tumor volume measurement and survival time(P<0.05).Conclusions:In a mouse orthotopic brain tumor model,the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.