| Redox regulation of P-glycoprotein-mediated multidrug resistance in multicellular prostate tumor spheroids. | |
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MedLine Citation:
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PMID: 10629088 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Multicellular prostate tumor spheroids develop intrinsic P-glycoprotein (Pgp)-mediated multidrug resistance with the appearance of quiescent cell areas. We have investigated the effect of intracellular reactive oxygen species (ROS) on Pgp expression in large, quiescent and drug-resistant multicellular spheroids (diameter 250 +/- 50microm). Using the ROS-sensitive fluorescence dye 2;7;-dichlorodihydrofluorescein diacetate (H(2)DCFDA), we demonstrated that these tumor spheroids are characterized by reduced intracellular ROS compared with drug-sensitive small spheroids (diameter 60 +/- 20microm) consisting predominantly of proliferating cells. The prooxidants hydrogen peroxide, menadione and glyceraldehyde raised ROS in large tumor spheroids and significantly down-regulated Pgp within 24 hr. Comparable effects were achieved with the known Pgp-reversing agents sodium orthovanadate, quinidine and cyclosporin A but not with verapamil. Consequently, the retention and toxicity of the anthracycline doxorubicin was increased in tumor spheroids treated with prooxidants. Co-administration of prooxidants and the free radical scavenger ebselen did not alter Pgp levels, indicating that down-regulation of Pgp is mediated via ROS. Down-regulation of Pgp by H(2)O(2) was abolished when either forskolin, 8-Br-cAMP or IBMX, which raise intracellular cAMP levels, was co-administered, indicating that Pgp expression is regulated by protein kinase A (PKA). Furthermore, Pgp was down-regulated by the PKA inhibitors Rp-cAMPs and H89. Since prooxidants stimulated the growth of multicellular spheroids and down-regulated the cyclin-dependent kinase inhibitor p27(kip1), we conclude that ROS-mediated Pgp down-regulation may be paralleled by recruitment of drug-resistant quiescent cells in the depth of the tumor tissue for cell-cycle activity. |
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Authors:
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M Wartenberg; K Fischer; J Hescheler; H Sauer |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: International journal of cancer. Journal international du cancer Volume: 85 ISSN: 0020-7136 ISO Abbreviation: Int. J. Cancer Publication Date: 2000 Jan |
Date Detail:
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Created Date: 2000-02-01 Completed Date: 2000-02-01 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 267-74 Citation Subset: IM |
Copyright Information:
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Copyright 2000 Wiley-Liss, Inc. |
Affiliation:
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Department of Neurophysiology, University of Cologne, Cologne, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology Cell Cycle / drug effects Cell Cycle Proteins* Cyclic AMP-Dependent Protein Kinases / metabolism Cyclin-Dependent Kinase Inhibitor p27 Doxorubicin / pharmacology Drug Resistance, Multiple* Drug Resistance, Neoplasm* Gene Expression Regulation, Neoplastic Glyceraldehyde / pharmacology Humans Hydrogen Peroxide / pharmacology Male Microtubule-Associated Proteins / biosynthesis, metabolism Oxidants / pharmacology* Oxidation-Reduction P-Glycoprotein / genetics, metabolism* Phenotype Prostatic Neoplasms / metabolism*, pathology Reactive Oxygen Species / metabolism* Spheroids, Cellular / drug effects*, metabolism, pathology Tumor Cells, Cultured Tumor Suppressor Proteins* Vitamin K / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Cell Cycle Proteins; 0/Microtubule-Associated Proteins; 0/Oxidants; 0/P-Glycoprotein; 0/Reactive Oxygen Species; 0/Tumor Suppressor Proteins; 12001-79-5/Vitamin K; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 23214-92-8/Doxorubicin; 367-47-5/Glyceraldehyde; 7722-84-1/Hydrogen Peroxide; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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