The epigallocatechin gallate derivative Y reverses drug resistance mediated by the ABCB1 transporter both and

Previously, we reported that Y, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin (DOX)--mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y in reversing drug resistance both and by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter (ABCB1 or P-glycoprotein, P-gp). Our results showed that Y significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mouse tumor xenograft model, Y (110 mg/kg, intragastric administration), in combination with doxorubicin (2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.

Combination of tetrandrine and paclitaxel overcomes multidrug resistance on C6/MDR glioma cells / 中草药

Objective To investigate the feasibility of tetrandrine combined with paclitaxel (PTX) in multidrug resistance reversal on C6/MDR glioma cells, and explore the potential molecular mechanisms. Methods Through the comparison of non-resistant glioma C6 cells and drug-resistant glioma C6/MDR cells, the cytotoxicity of against C6/MDR (or C6) cells were assayed by MTT method. The intracellular accumulation of PTX and Rhodamine 123 (R123) were determined by high performance liquid chromatography (HPLC) and flow cytometry, respectively. The cell apoptosis induction of C6/MDR (or C6) cells was detected by AnnexinV-PE/7-AAD staining method after various intervention of PTX, tetrandrine, and PTX + HfA. P-glycoprotein (P-gp) expression and P-gp ATPase activity were evaluated through P-gp antibody binding assay kit and Pgp-GloTM assay systems, respectively. Results The half maximal inhibitory concentration (IC50) of tetrandrine + PTX against C6/MDR cells were (5.88 ± 0.43) nmol/L. The C6/MDR intracellular accumulation of PTX and R123 were increased by 9.4-fold and 12.3-fold in the presence of 10 μmol/L tetrandrine. Accordingly, the apoptosis rate of C6/MDR cells treated with tetrandrine + PTX was 2.3-fold higher than PTX treatment. The tetrandrine-mediated multidrug resistance reversal was involved with the downregulation of P-gp expression and the stimulation of P-gp ATPase activity. Conclusion The combination of tetrandrine and PTX had a potential of overcoming multidrug resistance on C6/MDR glioma cells in vitro.

Insulin resistance of human hepatoma HepG2 cells and expression levels of FoxO1 mRNA and protein in reversal model and their significances / 吉林大学学报(医学版)

Objective: To study the expression levels of forkhead transcription factor(FoxO1) mRNA and protein in the insulin resistance (IR) HepG2 cells model (HepG2/IR) and IR reversal HepG2 cells model (HepG2/IR-PH), and to explore its mechanism in IR.Methods:The HepG2/IR was induced with different doses of insulin (1×10-10, 1×10-9, 1×10-8, 1×10-7, 1×10-6 and 1×10-5 mol·L-1) for different time(24, 36 and 48 h)in the HepG2 cells.The cells in control group were not treated with insulin.The glucose levels in supernant were determined by glucose oxidase method, and the glucose consumption in HepG2 in various groups were calculated to confirm the optimum induction conditions of HepG2/IR.The HepG2/IR-PH was induced with different doses of pioglitazone hydrochloride (PH) (0.156, 0.313, 0.625, 1.250, 2.500, 5.000, 10.000 and 20.000 mmol·L-1) in the HepG2 cells, and control group was set up at the same time. The proliferation activities of cells were observed by MTT assay to confirm the optimum reversal concentration of PH.The FoxO1 mRNA and protein expression levels were detected by Real-time PCR and Western blotting methods.Results: The glucose consumption decreased by 45.84% in HepG2/IR after treated with 1×10-7 mol·L-1 insulin for 36 h, and there was significant difference compared with control group(P0.05).Compared with control group, the expression levels of FoxO1 mRNA and protein in HepG2/IR were significantly increased(P0.05).Conclusion:The IR of HepG2/IR is associated with the FoxO1 mRNA expression.The detection of FoxO1 mRNA seems to be an indicator to evaluate the efficacy of insulin sensitizer, and inhibiting the expression of FoxO1 mRNA may be developed as a potential therapy for type 2 diabetes.

Reversal of breast cancer multidrug resistance in Vitro by doxorubicin and elacridar co-delivery nanop-article / 中国药学杂志

OBJECTIVE: To prepare a redox and pH dual sensitive nano-carrier based on PAMAM in order to co-loading chemotherapeutics doxorubicin and breast cancer multidrug resistance reversal agent elacridar, and study their in vitro reversal effect. METHODS: The infrared spectrum FTIR was used to characterize the carrier. Confocal was used to investigate the intracellular triggered drug release. The reversal effect of breast cancer multidrug resistance and the in vitro anti-tumor activity of doxorubicin and elacridar co-loaded nanoparticles were investigated using flow cytometry and cell toxicity tests, respectively. RESULTS: The doxorubicin and elacridar co-loaded nanoparticles (PSSP/DOX/ELC) were successfully prepared, and pH-redox dual sensitive of carrier was proved by cell experiments. And the carrier was uptaken into cells and delivery to lysosome, and drug release was triggered in the lysosome acid condition, then the released drug diffused to the nucleus. The trial of rhodamine 123 accumulation and efflux assay revealed that the accumulation of rhodamine 123 was notably increased after incubation of elacridar in MCF-7/ADR cells. The cytotoxicity of PSSP/DOX/ELC nanoparticles against MCF-7/ADR cell line was significantly stronger than that of either free doxorubicin or only doxorubicin loaded nanoparticles (PSSP/DOX). CONCLUSION: The reversal effect of multidrug resistance and the cytotoxicity of cancer cells were significantly enhanced by PSSP/DOX/ELC nanoparticles. PSSP/ DOX/ELC nanoparticles is a promising delivery system.

Electric stimulations mediated beta lactam resistance reversal and correlation with growth dynamics of community acquired methicillin resistant Staphylococcus aureus.

The community associated methicillin resistant Staphylococcus aureus (CA-MRSA) is a serious issue of public health. Here, we conducted an experimental approach to determine: (i) the optimal significant stimulation range of electrical current for effective checking of CA-MRSA growth; (ii) the effect of electrical stimulations on methicillin susceptibility and possible beta lactam resistance reversal; and (iii) the variation in the level of ATP as function of exposure to electric current. An 8 chambered electrical system was developed for DC flow in control and test sets, with and without drug (oxacillin 4 mg/ml). Measurement of growth by CFU/ml and spectrometry, susceptibility and ATP levels were calculated and interpreted. Linear pattern in reduction of ATP was observed with respect to the intensity of electric current (EC) and an enhanced inhibitory effect was explicit with 1000 microampere (μA) with 30 min exposure. At 4000 μA exposure to DC at 180 min and in combination of drug (μA+D), the growth of CA-MRSA was substantially checked to 0.23 absorbance in comparison to current without drug and the effect of DC electrical current to the culture showed that 10 μA, 100 μA and 4000 μA current exposure in combination of oxacillin (μA+D), markedly reduced the CFU to an average of 256.4. ATP level was linearly reduced with exposure to EC.

Enhancement of the antimalarial efficacy of amodiaquine by chlorpheniramine in vivo

Resistance in Plasmodium falciparum to amodiaquine (AQ) can be reversed in vitro with with antihistaminic and tricyclic antidepressant compounds, but its significance in vivo is unclear. The present report presents the enhancement of the antimalarial efficacy of AQ by chlorpheniramine, an H1 receptor antagonist that reverses chloroquine (CQ) resistance in vitro and enhances its efficacy in vivo, in five children who failed CQ and/or AQ treatment, and who were subsequently retreated and cured with a combination of AQ plus CP, despite the fact that parasites infecting the children harboured mutant pfcrtT76 and pfmdr1Y86 alleles associated with AQ resistance. This suggests a potential clinical appliation of the reversal phenomenon.

Reversal of Multidrug Resistance Gene mdr1 of Drug-Resistant Human Hepatocellular Carcinoma Cells with Antisense Oligodeoxynucleotide in Vivo / 中国普外基础与临床杂志

Objective To investigate the reversal of the multidrug resistant gene mdr1 in vivo by antisense oligodeoxynucleotide (ASODN) on the basis of study in vitro. Methods The cultured drug-resistant human hepatocellular carcinoma cells were injected under the skin of axilla to establish the tumor model of nude mice. mdr1 ASODN accompanied by Lipofectamine were injected locally and ADM was injected intraperitoneally. Control 1 and control 2 were locally injected by Lipofectamine and normal saline separately, and ADM was also injected intraperitoneally. Results As time went on the tumor size increased and from the 5th day on alterations were marked, tumor size in different time phase showed marked difference to the prior time phase with significant difference (P 0.05). The results suggested that SODN and Lipofectamine showed no marked effect on tumor growth of nude mice and ASODN had marked inhibition effect on tumor growth.Conclusion mdr1 ASODN can also reverse multidrug resistance of drug-resistant human hepatocellular carcinoma cells in vivo. After the treatment the tumor’s growth in nude mice will slow down in a range of time.