Interaction of Docetaxel (“Taxotere”) with Human P‐Glycoprotein

Shirakawa, Kiyoshi; Takara, Kohji; Tanigawara, Yusuke; Aoyama, Nobuo; Kasuga, Masato; Komada, Fusao; Sakaeda, Toshiyuki; Okumura, Katsuhiko

doi:10.1111/j.1349-7006.1999.tb00723.x

Cited by 68 publications

(45 citation statements)

References 25 publications

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“…In the 1990s, itraconazole was demonstrated to reverse chemoresistance in cancer cells overexpressing P-gp ( Fig. 1; Table I) (4)(5)(6). In addition, the human breast cancer resistance protein is also inhibited by itraconazole (7).…”

Section: Preclinical Datamentioning

confidence: 99%

Repurposing itraconazole as an anticancer agent

et al. 2017

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Abstract. Itraconazole, a common anti-fungal agent, has demonstrated potential anticancer activity, including reversing chemoresistance mediated by P-glycoprotein, modulating the signal transduction pathways of Hedgehog, mechanistic target of rapamycin and Wnt/β-catenin in cancer cells, inhibiting angiogenesis and lymphangiogenesis, and possibly interfering with cancer-stromal cell interactions. Clinical trials have suggested the clinical benefits of itraconazole monotherapy for prostate cancer and basal cell carcinoma, as well as the survival advantage of combination chemotherapy for relapsed non-small cell lung, ovarian, triple negative breast, pancreatic and biliary tract cancer. As drug repurposing is cost-effective and timesaving, a review was conducted of preclinical and clinical data focusing on the anticancer activity of itraconazole, and discusses the future directions for repurposing itraconazole as an anticancer agent.

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Section: Preclinical Datamentioning

confidence: 99%

Repurposing itraconazole as an anticancer agent

et al. 2017

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“…Docetaxel is also a substrate of P-gp, first shown in 1994 by Wils et al [109,110]. Because of the encouraging results obtained with paclitaxel in combination with P-gp inhibitors, studies in mice were also performed with docetaxel.…”

Section: Docetaxelmentioning

confidence: 99%

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

2002

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The oral bioavailability of many cytotoxic drugs is low and/or highly variable. This can be caused by high affinity for drug transporters and activity of metabolic enzymes in the gastrointestinal tract and liver. In this review, we will describe the main involved drug transporters and metabolic enzymes and discuss novel methods to improve oral treatment of affected substrate drugs. Results of preclinical and clinical phase I and II studies will be discussed in which affected substrate drugs, such as paclitaxel, docetaxel, and topotecan, are given orally in combination with an inhibitor of drug transport or drug metabolism. Future randomized studies will, hopefully, confirm that this strategy for oral treatment is at least as equally effective and safe as standard intravenous administration of these drugs. The Oncologist 2002;7:516-530

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“…It protects the human body from xenobiotics by suppressing intestinal absorption and excretion into the urine and bile and limits central nervous system entry (Thiebaut et al, 1987). MDR1 shows a wide spectrum of substrate specificities, and many substrates are hydrophobic organic cations, including anticancer drugs such as vinca alkaloids and taxanes (Shirakawa et al, 1999;Borst and Elferink, 2002). For this reason, overexpression of MDR1 in cancer cells is the primary cause of multidrug resistance to its substrate drugs (Gottesman and Pastan, 1993;Ambudkar et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Utility of P-Glycoprotein and Organic Cation Transporter 1 Double-Transfected LLC-PK1 Cells for Studying the Interaction of YM155 Monobromide, Novel Small-Molecule Survivin Suppressant, with P-Glycoprotein

Iwai¹,

Minematsu²,

Li³

et al. 2011

Drug Metab Dispos

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ABSTRACT:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide), a novel small molecule that downregulates survivin and exhibits potent antitumor activity, is hydrophilic and cationic. Although previous studies have shown that influx transporters play important roles in the uptake of YM155 into hepatocytes and possibly into cancer cells, efflux transporters have yet to be investigated. In this study, we assessed the interaction of YM155 with P-glycoprotein [multidrug resistance 1 (MDR1)/ATP-binding cassette B1] using two kinds of transcellular transport systems: Caco-2 and MDR1-expressing LLC-PK1 cells (LLC-MDR1). We also used a newly established LLC-OCT1/MDR1 cell line, which expresses basal YM155 uptake transporter organic cation transporter1 (OCT1) and apical MDR1. Direct interaction between YM155 and MDR1 and other efflux transporters was evaluated using transporter-expressing membrane vesicles. A bidirectional transporter assay using Caco-2 and LLC-MDR1 cells showed low permeability and no vectorial transport of YM155, suggesting that YM155 is not a substrate of MDR1. However, vectorial transport across LLC-OCT1/MDR1 cells was identified, which was inhibited by the MDR1 inhibitor cyclosporine A, clearly indicating that YM155 is in fact a substrate of MDR1. Insufficient expression of basal uptake transporter of YM155 in Caco-2 and LLC-MDR1 might have confounded conclusions regarding YM155 and MDR1. Using the transporter-expressing vesicles, MDR1-mediated transport was most significantly involved in YM155 transport among the efflux transporters examined. In conclusion, these findings suggest that YM155 is a substrate of MDR1, and that MDR1 may play an important role in the pharmacokinetics of YM155. Transcellular assays lacking basal uptake transporters may be inaccurate in the assessment of hydrophilic compounds that have poor membrane permeability by passive diffusion.

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Interaction of Docetaxel (“Taxotere”) with Human P‐Glycoprotein

Cited by 68 publications

References 25 publications

Repurposing itraconazole as an anticancer agent

Repurposing itraconazole as an anticancer agent

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

Utility of P-Glycoprotein and Organic Cation Transporter 1 Double-Transfected LLC-PK1 Cells for Studying the Interaction of YM155 Monobromide, Novel Small-Molecule Survivin Suppressant, with P-Glycoprotein

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