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.

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.

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 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

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

Pyronaridine, a novel modulator of P-glycoprotein-mediated multidrug resistance in tumor cells in vitro and in vivo

2004 ◽  
Vol 319 (4) ◽  
pp. 1124-1131 ◽  
Author(s):  
Jing Qi ◽  
Shubin Wang ◽  
Guying Liu ◽  
Hui Peng ◽  
Jinhong Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Tumor Cells ◽  
P Glycoprotein

Perspectives of inhibition of multidrug resistance during cancer chemotherapy, in vitro and in vivo experiments

2009 ◽  
Vol 150 (13) ◽  
pp. 607-614
Author(s):  
Helga Engi
Keyword(s):  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
In Vivo Experiments

A daganatos megbetegedések elleni küzdelem hatásosságában a multidrog-rezisztencia kérdésének megoldása fontos szerepet játszik. Növekvő igény mutatkozik olyan új vegyületek kifejlesztésére, amelyek képesek gátolni a különböző rezisztenciamechanizmusokat. Célul tűztük ki a szintetikus (cinnamilidén-ketonok; 1,4-dihidropiridin és fenotiazinszármazékok; hősokkfehérje-90-gátló peptidek és Tilozin betti bázisú származék), valamint természetes ( Euphorbia -diterpének) növényi alkotókból kivont származékok multidrog-rezisztenciáért felelős effluxpumpa-gátlásának vizsgálatát különböző sejtvonalakon, remélve, hogy a verapamiltól kevésbé toxikus, de annál hatásosabb rezisztenciamódosító vegyületeket találunk. A tézis első része a vizsgált vegyületek P-glikoprotein effluxpumpa-gátló hatását mutatja be különböző sejtvonalakon. Általánosságban elmondható, hogy az újonnan azonosított rezisztenciamódosító vegyületek képesek voltak a kiválasztott rákellenes szerek sejtszaporodás-gátló hatásának fokozására, köcsönhatásuk szinergizáló vagy additív hatást mutatott in vitro kísérletekben. A Tilozin betti bázisú származék in vitro kísérletekben tapasztalt hatását, további in vivo , DBA/2 egér modellek alátámasztották. Az antitumorhatás vizsgálatának egy alternatív útja a különböző vegyületekkel kiváltott apoptózis folyamata. A legígéretesebb apoptózisindukálónak a dihidropiridin 13 bizonyult. A latrán vegyületek antipromóciós hatásának in vitro modellezéséhez humán cytomegalovirussal fertőzött humán tüdőráksejteket használtunk. A vizsgált makrociklikus latrán típusú diterpén vegyületek többsége, kivéve a latilagascene D vegyület, képes volt a cytomegalovirus korai antigén-kifejeződésének gátlására.

scholarly journals A new substrate triggers susceptibility by uncoupling a bacterial multidrug resistance efflux pump

2021 ◽  
Author(s):  
Peyton J. Spreacker ◽  
Nathan E. Thomas ◽  
Will F. Beeninga ◽  
Merissa Brousseau ◽  
Kylie M. Hibbs ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Multidrug Resistance ◽  
Efflux Pump ◽  
Molecular Transport ◽  
Drug Susceptibility ◽  
Secondary Site ◽  
Antibiotic Development ◽  
E Coli

AbstractSmall multidrug resistance (SMR) transporters perform coupled antiport of protons and toxic substrates, contributing to antibiotic resistance through efflux of these compounds from the bacterial cytoplasm. Extensive biophysical studies of the molecular transport mechanism of the E. coli SMR transporter EmrE indicate that it should also be capable of performing proton/drug symport or uniport, either of which will lead to drug susceptibility rather than drug resistance in vivo. Here we show that EmrE does indeed confer susceptibility to some small molecule substrates in the native E. coli in addition to conferring resistance to known polyaromatic cation substrates. In vitro experiments show that substrate binding at a secondary site triggers uncoupled proton uniport that leads to susceptibility. These results suggest that the SMR transporters provide one avenue for bacterial-selective dissipation of the proton-motive force. This has potential for antibiotic development and disruption of antibiotic resistance due to drug efflux more broadly.

scholarly journals SDZ 280-446, a novel semi-synthetic cyclopeptolide: in vitro and in vivo circumvention of the P-glycoprotein-mediated tumour cell multidrug resistance

1992 ◽  
Vol 65 (1) ◽  
pp. 11-18 ◽  
Author(s):  
F Loor ◽  
D Boesch ◽  
C Gavériaux ◽  
B Jachez ◽  
A Pourtier-Manzanedo ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Tumour Cell ◽  
P Glycoprotein

scholarly journals Geniposide reverses multidrug resistance in vitro and in vivo by inhibiting the efflux function and expression of P-glycoprotein

2016 ◽  
Vol 13 (2) ◽  
pp. 437-442 ◽  
Author(s):  
Hefei Huang ◽  
Xuenong Zhang ◽  
Zhixiong Huang ◽  
Ye Zhang ◽  
Zhiyong Zhou
Keyword(s):  
Multidrug Resistance ◽  
P Glycoprotein
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