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.

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 Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo

2022 ◽  
Vol 12 ◽  
Author(s):  
Gangyang Wang ◽  
Lingling Cao ◽  
Yafei Jiang ◽  
Tao Zhang ◽  
Hongsheng Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Mouse Model ◽  
Atpase Activity ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Protein Expression Level ◽  
Nude Mouse Model ◽  
P Glycoprotein

Overexpression of the multidrug resistance (MDR)-related protein P-glycoprotein (PGP1), which actively extrudes chemotherapeutic agents from cells and significantly decreases the efficacy of chemotherapy, is viewed as a major obstacle in osteosarcoma chemotherapy. Anlotinib, a novel tyrosine kinase inhibitor (TKI), has good anti-tumor effects in a variety of solid tumors. However, there are few studies on the mechanism of anlotinib reversing chemotherapy resistance in osteosarcoma. In this study, cellular assays were performed in vitro and in vivo to evaluate the MDR reversal effects of anlotinib on multidrug-resistant osteosarcoma cell lines. Drug efflux and intracellular drug accumulation were measured by flow cytometry. The vanadate-sensitive ATPase activity of PGP1 was measured in the presence of a range of anlotinib concentrations. The protein expression level of ABCB1 was detected by Western blotting and immunofluorescence analysis. Our results showed that anlotinib significantly increased the sensitivity of KHOSR2 and U2OSR2 cells (which overexpress PGP1) to chemotherapeutic agents in vitro and in a KHOSR2 xenograft nude mouse model in vivo. Mechanistically, anlotinib increases the intracellular accumulation of PGP1 substrates by inhibiting the efflux function of PGP1 in multidrug-resistant cell lines. Furthermore, anlotinib stimulated the ATPase activity of PGP1 but affected neither the protein expression level nor the localization of PGP1. In animal studies, anlotinib in combination with doxorubicin (DOX) significantly decreased the tumor growth rate and the tumor size in the KHOSR2 xenograft nude mouse model. Overall, our findings suggest that anlotinib may be useful for circumventing MDR to other conventional antineoplastic drugs.

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

scholarly journals A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 848 ◽  
Author(s):  
Anna Lucia Fallacara ◽  
Claudio Zamperini ◽  
Ana Podolski-Renić ◽  
Jelena Dinić ◽  
Tijana Stanković ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Multidrug Resistant ◽  
Cellular Level ◽  
Cns Tumors ◽  
Significant Activity ◽  
Src Tyrosine Kinase ◽  
P Glycoprotein ◽  
New Strategy

Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells’ membrane of the blood-brain barrier, where it limits drug delivery to central nervous system (CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp at the cellular level. The tested compounds were found to increase the intracellular accumulation of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against glioblastoma.

Synthesis and biological evaluation of carbon-substituted C-4 derivatives of podophyllotoxin

1996 ◽  
Vol 74 (9) ◽  
pp. 1704-1708 ◽  
Author(s):  
Yvonne Lear ◽  
Tony Durst
Keyword(s):  
Antitumour Activity ◽  
Human Colon ◽  
Boron Trifluoride Etherate ◽  
Multidrug Resistant ◽  
Resistant Cell ◽  
Biological Evaluation ◽  
Colon Cell ◽  
Colon Cell Line

Several C-4 carbon-substituted analogues of podophyllotoxin, 1, were prepared by treatment of 1 with allyltrimethylsilane or trimethylsilylcyanide in the presence of boron trifluoride etherate. Alternatively, carbon substituents were introduced via additions to the carbobenzyloxy-protected C-4′-dimethylated podophyllotoxone. These 4′-dimethylated derivatives showed promising in vitro antitumour activity and were equally active against human colon cell line HT116 and two multidrug resistant cell lines. The alcohol 6 was evaluated in vivo but was found to be inactive. Key words: podophyllotoxin analogues, podophyllotox-4-one, C4 carbon substituted podophyllotoxins.

5009 ORAL Significant antitumour activity of the novel epothilone ZK-EPO against in vitro and in vivo models of ovarian cancer

2007 ◽  
Vol 5 (4) ◽  
pp. 313-314 ◽  
Author(s):  
S. Hammer ◽  
N. Arnold ◽  
F. Hilpert ◽  
K. Bräutigam ◽  
A. Sommer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Antitumour Activity ◽  
The Novel ◽  
In Vivo Models

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.

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