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

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.

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

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0518 ◽

2017 ◽

Vol 95 (5) ◽

pp. 580-585 ◽

Cited By ~ 2

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.

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

Bioscience Reports ◽

10.1042/bsr20120020 ◽

2012 ◽

Vol 32 (6) ◽

pp. 559-566 ◽

Cited By ~ 19

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.

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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

Cancer Letters ◽

10.1016/j.canlet.2018.10.020 ◽

2019 ◽

Vol 442 ◽

pp. 91-103 ◽

Cited By ~ 9

Author(s):

Albert A. De Vera ◽

Pranav Gupta ◽

Zining Lei ◽

Dan Liao ◽

Silpa Narayanan ◽

...

Keyword(s):

Multidrug Resistance ◽

Glycoprotein P ◽

P Glycoprotein

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

PLoS ONE ◽

10.1371/journal.pone.0116886 ◽

2015 ◽

Vol 10 (2) ◽

pp. e0116886 ◽

Cited By ~ 6

Author(s):

Zheyi Hu ◽

Zaigang Zhou ◽

Yahui Hu ◽

Jinhui Wu ◽

Yunman Li ◽

...

Keyword(s):

Multidrug Resistance ◽

P Glycoprotein

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

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2004.05.099 ◽

2004 ◽

Vol 319 (4) ◽

pp. 1124-1131 ◽

Cited By ~ 28

Author(s):

Jing Qi ◽

Shubin Wang ◽

Guying Liu ◽

Hui Peng ◽

Jinhong Wang ◽

...

Keyword(s):

Multidrug Resistance ◽

Tumor Cells ◽

P Glycoprotein

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

Orvosi Hetilap ◽

10.1556/oh.2009.28358 ◽

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.

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