Reversal effect of itraconazole on adriamycin and etoposide resistance in human leukemia cells

Kurosawa, M; Okabe, Mihiro; Hara, Noboru; Kawamura, Ken-ichi; Suzuki, Shinya; Sakurada, Keisuke; Asaka, Masahiro

doi:10.1007/bf00663011

Cited by 32 publications

(27 citation statements)

References 13 publications

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“…The mechanism of the itraconazole-methylprednisolone interaction is probably inhibition of CYP3ACmediated metabolism of methylprednisolone. However, itraconazole can also inhibit P-glycoprotein (Kurosawa et al 1996), a transmembrane efflux pump, and methylprednisolone has been recently shown to be a P-glycoprotein substrate (Saitoh et a/. 1998).…”

Section: Discussionmentioning

confidence: 99%

Itraconazole Decreases the Clearance and Enhances the Effects of Intravenously Administered Methylprednisolone in Healthy Volunteers

Varis

Kivistö

Backman

et al. 1999

Pharmacology & Toxicology

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A possible interaction of itraconazole, a potent inhibitor of CYP3A4, with intravenously administered methylprednisolone, was examined. In this double-blind, randomized, two-phase cross-over study, 9 healthy volunteers received either 200 mg itraconazole or matched placebo orally once a day for 4 days. On day 4, a dose of 16 mg methylprednisolone as sodium succinate was administered intravenously. Plasma concentrations of methylprednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined up to 24 hr. itraconazole increased the total area under the plasma methylprednisolone concentration-time curve (AUC(0-m) 2.6-fold) (P

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Section: Discussionmentioning

confidence: 99%

Itraconazole Decreases the Clearance and Enhances the Effects of Intravenously Administered Methylprednisolone in Healthy Volunteers

Varis

Kivistö

Backman

et al. 1999

Pharmacology & Toxicology

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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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“…Itraconazole can also reverse resistance to the P-gp substrate daunorubicin (DNR) in a murine acute leukemia cell line in vitro (multidrug-resistant cells) (13), while the methylthiazolyl diphenyltetrazolium bromide (MTT) cytotoxicity assay results suggest an interaction of itraconazole with MDR and/or multidrug resistance protein (MRP)-associated resistance because of resistance reversal (18). The transport of vinblastine, DNR, and doxorubicin is affected by 100 M itraconazole in cells transfected with MDR1 cDNA (31).…”

mentioning

confidence: 99%

Interaction of Common Azole Antifungals with P Glycoprotein

Wang¹,

Lew²,

Casciano³

et al. 2002

Antimicrob Agents Chemother

213

151

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Both eucaryotic and procaryotic cells are resistant to a large number of antibiotics because of the activities of export transporters. The most studied transporter in the mammalian ATP-binding cassette transporter superfamily, P glycoprotein (P-gp), ejects many structurally unrelated amphiphilic and lipophilic xenobiotics. Observed clinical interactions and some in vitro studies suggest that azole antifungals may interact with P-gp. Such an interaction could both affect the disposition and exposure to azole antifungal therapeutics and partially explain the clinical drug interactions observed with some antifungals. Using a whole-cell assay in which the retention of a marker substrate is evaluated and quantified, we studied the abilities of the most widely prescribed orally administered azole antifungals to inhibit the function of this transporter. In a cell line presenting an overexpressed amount of the human P-gp transporter, itraconazole and ketoconazole inhibited P-gp function with 50% inhibitory concentrations (IC 50 s) of ϳ2 and ϳ6 M, respectively. Cyclosporin A was inhibitory with an IC 50 of 1.4 M in this system. Uniquely, fluconazole had no effect in this assay, a result consistent with known clinical interactions. The effects of these azole antifungals on ATP consumption by P-gp (representing transport activity) were also assessed, and the K m values were congruent with the IC 50 s. Therefore, exposure of tissue to the azole antifungals may be modulated by human P-gp, and the clinical interactions of azole antifungals with other drugs may be due, in part, to inhibition of P-gp transport.

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Reversal effect of itraconazole on adriamycin and etoposide resistance in human leukemia cells

Cited by 32 publications

References 13 publications

Itraconazole Decreases the Clearance and Enhances the Effects of Intravenously Administered Methylprednisolone in Healthy Volunteers

Itraconazole Decreases the Clearance and Enhances the Effects of Intravenously Administered Methylprednisolone in Healthy Volunteers

Repurposing itraconazole as an anticancer agent

Interaction of Common Azole Antifungals with P Glycoprotein

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