Reversal of P-glycoprotein-mediated multidrug resistance and pharmacokinetics study in rats by WYX-5

2017 ◽  
Vol 95 (5) ◽  
pp. 580-585 ◽  
Author(s):  
Yuzhu Wang ◽  
Jian Cui ◽  
Yuxuan Dai ◽  
Yuxiang Wu ◽  
Wenlong Huang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Therapeutic Index ◽  
Glycoprotein P ◽  
Reversal Effect ◽  
P Glycoprotein ◽  
Relative Safety ◽  
Reversal Mechanism ◽  
Low Cytotoxicity

Multidrug resistance (MDR) is one of the major obstacles confronted in cancer chemotherapy; this obstacle is mainly due to the overexpression of P-glycoprotein (P-gp). Co-administration of anticancer drugs and P-gp inhibitors is a promising approach to overcome MDR. WYX-5, a novel P-gp inhibitor, shows a notable reversal effect with low cytotoxicity in vitro. In this paper, the reversal mechanism and safety of the MDR modulator WYX-5 were explored in vitro, and evaluated for its pharmacokinetics and effects on adriamycin (ADM) metabolism in vivo. The results suggest that WYX-5 is a potent P-gp inhibitor with EC50 in nanomole range (EC50 = 204.3 ± 20.2 nmol·L−1), relative safety (therapeutic index = 446.4), which performs as a substrate of P-gp and retrains its function. Further, WYX-5 (5 mg·kg−1) had relatively ideal pharmacokinetic properties (T1/2 = 6.448 h, F = 96.05%) without interactions with ADM metabolism in vivo. In conclusion, WYX-5 may be a promising candidate for MDR cancer combined-chemotherapy research.

Reversal of P-glycoprotein-medicated multidrug resistance by LBM-A5 in vitro and a study of its pharmacokinetics in vivo

2015 ◽  
Vol 93 (1) ◽  
pp. 33-38 ◽  
Author(s):  
Tianxiao Zhao ◽  
Yun Song ◽  
Baomin Liu ◽  
Qianqian Qiu ◽  
Lei Jiao ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
Anticancer Agents ◽  
Efflux Pump ◽  
Therapeutic Index ◽  
Intracellular Accumulation ◽  
P Glycoprotein ◽  
Reversal Mechanism

The overexpression of P-glycoprotein (P-gp) in tumors leads to multidrug resistance (MDR), which is a significant obstacle in clinical cancer chemotherapy. The co-administration of anticancer drugs and MDR modulators is a promising strategy for overcoming this problem. Our study aimed to explore the reversal mechanism and safety of the MDR modulator LBM-A5 in vitro, and evaluate its pharmacokinetics and effects on doxorubicin metabolism in vivo. We evaluated an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of anticancer agents mediated by LBM-A5, the effect of LBM-A5 on rhodamine123 intracellular accumulation, and the efflux in K562/DOX cells to investigate the reversal mechanisms of LBM-A5. The results showed that LBM-A5 inhibits rhodamine123 efflux and increases intracellular accumulation by inhibiting the efflux pump function of P-gp. Furthermore, the therapeutic index and CYP3A4 activity analysis in vitro suggested that LBM-A5 is reasonably safe to use. Also, LBM-A5 (10 mg/kg body mass) achieved the required plasma concentration in sufficient time to reverse MDR in vivo. Importantly, the LBM-A5 treatment group shared similar doxorubicin (DOX) pharmacokinetics with the free DOX group. Our results suggest that LBM-A5 effectively reverses MDR (EC50 = 483.6 ± 81.7 nmol·L−1) by inhibiting the function of P-gp, with relatively ideal pharmacokinetics and in a safe manner, and so may be a promising candidate for cancer chemotherapy research.

scholarly journals Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo

2019 ◽  
Vol 442 ◽  
pp. 91-103 ◽  
Author(s):  
Albert A. De Vera ◽  
Pranav Gupta ◽  
Zining Lei ◽  
Dan Liao ◽  
Silpa Narayanan ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein

Effect of Tetrandrine and Toremifene on the Reversion of Multidrug Resistance of K562/A02 Cell Line

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5063-5063
Author(s):  
Bao-An Chen ◽  
Qiu-xia Zhao ◽  
Jian Cheng ◽  
Feng Gao ◽  
Wen-lin Xu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cell Line ◽  
K562 Cells ◽  
Mrna Levels ◽  
Survivin Mrna ◽  
Glycoprotein P ◽  
Reversal Effect ◽  
Protein Levels ◽  
Reversal Mechanism

Abstract Objective: To study the reversal effect of Tetrandrine(Tet) and the estrogen-receptor inhibitor,toremifene(Tor),on multidrug resistance cell line K562/A02 and to investigate the reversal mechanism of this combination. Methods: ADM accumulation and the apoptosis percentage of K562 and K562/A02 cells were analyzed by fluorospectrophotometry, respectively. The protein levels of P-glycoprotein (P-gp) were detected by fluorospectrophotometry. The mRNA levels of mdr1 and Survivin were determined by RT-PCR. Results: The IC50 of ADM for K562/A02 and K562 cells were 57.43±4.55mg/L and 1.16±0.05mg/L respectively. Pretreating K562/A02 cells with toremifene(2.5μmol/L) or Tet(1μmol/L) for 72 hours partially restored the sensitivity of K562/A02 cells to ADM (IC50 were 20.74±1.62mg/L and 14.12±1.20mg/L respectively) but had no effect on K562 cells; IC50 of combined tetrandrine and toremifene was 9.14±1.03mg/L;K562/A02 showed apoptotic characteristics after treated with tetrandrine, toremifene (alone or combination);tetrandrine and toremifene (alone or combination) elevated the intracellular ADM accumulation in K562/A02; P-gp, mdr1 and Survivin mRNA were down regulated. Conclusion: Tetrandrine, toremifene (alone or combination) showed significant MDR reversal activity in vitro The reversal activity may be related to the inhibition of P-gp overexpression and down regulation the expression of mdr1 and Survivin mRNA to increase the intracellular accumulation of anticancer drugs, which lead to more K562/A02 cells apoptosis; Multidrug resistance (MDR) can be partially reversed by Tet or Tor of which the combination shows a great synergistic reversal effect.

scholarly journals Overcoming multidrug-resistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416

2012 ◽  
Vol 32 (6) ◽  
pp. 559-566 ◽  
Author(s):  
Yan Xu ◽  
Feng Zhi ◽  
Guangming Xu ◽  
Xiaolei Tang ◽  
Sheng Lu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
Antitumour Activity ◽  
Multidrug Resistant ◽  
The Novel ◽  
Mice Model ◽  
P Glycoprotein ◽  
Channel Currents

MDR (multidrug-resistance) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by overexpression of P-gp (P-glycoprotein). Much effort has been devoted to developing P-gp inhibitors to modulate MDR. However, none of the inhibitors on the market have been successful. 1416 [1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (phenoprolamine hydrochloride)] is a new VER (verapamil) analogue with a higher IC50 for blocking calcium channel currents than VER. In the present paper, we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of VBL (vinblastine) in P-gp-overexpressed human multidrug-resistant K562/ADM (adriamycin) and KBV cells, but had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rh123 (rhodanmine123) content in MDR cells. Human K562/ADM xenograft-nude mice model verified that 1416 potentiates the antitumour activity of VBL in vivo. RT-PCR (reverse transcriptase-PCR) and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggest that 1416 could be a promising agent for overcoming MDR in cancer chemotherapy.

scholarly journals Upregulations of Clcn3 and P-Gp Provoked by Lens Osmotic Expansion in Rat Galactosemic Cataract

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
Lixia Ji ◽  
Lixia Cheng ◽  
Zhihong Yang
Keyword(s):  
Osmotic Stress ◽  
Early Stage ◽  
Lens Epithelial Cells ◽  
Anterior Capsule ◽  
Glycoprotein P ◽  
Protein Levels ◽  
P Glycoprotein ◽  
Sugar Cataract

Objective.Lens osmotic expansion, provoked by overactivated aldose reductase (AR), is the most essential event of sugar cataract. Chloride channel 3 (Clcn3) is a volume-sensitive channel, mainly participating in the regulation of cell fundamental volume, and P-glycoprotein (P-gp) acts as its modulator. We aim to study whether P-gp and Clcn3 are involved in lens osmotic expansion of galactosemic cataract.Methods and Results.In vitro, lens epithelial cells (LECs) were primarily cultured in gradient galactose medium (10–60 mM), more and more vacuoles appeared in LEC cytoplasm, and mRNA and protein levels of AR, P-gp, and Clcn3 were synchronously upregulated along with the increase of galactose concentration. In vivo, we focused on the early stage of rat galactosemic cataract, amount of vacuoles arose from equatorial area and scattered to the whole anterior capsule of lenses from the 3rd day to the 9th day, and mRNA and protein levels of P-gp and Clcn3 reached the peak around the 9th or 12th day.Conclusion. Galactosemia caused the osmotic stress in lenses; it also markedly leads to the upregulations of AR, P-gp, and Clcn3 in LECs, together resulting in obvious osmotic expansion in vitro and in vivo.

scholarly journals Pharmacokinetic Alteration of Paclitaxel by Ferulic Acid Derivative

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 593 ◽  
Author(s):  
Jaeok Lee ◽  
Song Wha Chae ◽  
LianJi Ma ◽  
So Yeon Lim ◽  
Sarah Alnajjar ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Ferulic Acid ◽  
Acid Derivative ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Substrate Drug

P-glycoprotein (P-gp) is known to be involved in multidrug resistance (MDR) and modulation of pharmacokinetic (PK) profiles of substrate drugs. Here, we studied the effects of synthesized ferulic acid (FA) derivatives on P-gp function in vitro and examined PK alteration of paclitaxel (PTX), a well-known P-gp substrate drug by the derivative. Compound 5c, the FA derivative chosen as a significant P-gp inhibitor among eight FA candidates by in vitro results, increased PTX AUCinf as much as twofold versus the control by reducing PTX elimination in rats. These results suggest that FA derivative can increase PTX bioavailability by inhibiting P-gp existing in eliminating organs.

scholarly journals HZ08 Reverse P-Glycoprotein Mediated Multidrug Resistance In Vitro and In Vivo

PLoS ONE ◽  
2015 ◽  
Vol 10 (2) ◽  
pp. e0116886 ◽  
Author(s):  
Zheyi Hu ◽  
Zaigang Zhou ◽  
Yahui Hu ◽  
Jinhui Wu ◽  
Yunman Li ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
P Glycoprotein
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