Linked Life Data

11454692

Source:http://linkedlifedata.com/resource/pubmed/id/11454692

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2001-7-16
pubmed:abstractText
We examined the role of multidrug resistance protein (MRP) 1 (ABCC1) in the emergence of mitoxantrone (MX) cross-resistance in a MCF7 breast cancer cell line selected for resistance to etoposide. The resistant cell line, MCF7/VP, expresses high levels of MRP1, whereas the parental cell line, MCF7/WT, does not. MCF7/VP cells are 6-10-fold cross-resistant to MX when compared with MCF7/WT cells. Drug transport studies in intact MCF7/VP cells revealed that MX resistance is associated with reduced MX accumulation due to enhanced MX efflux. MX efflux is ATP dependent and inhibited by sulfinpyrazone and cyclosporin A. Inhibition of MX efflux with these agents sensitizes cells to MX cytotoxicity and partially reverses MX resistance in MCF7/VP cells. Whereas resistance is partially attributable to increased MX efflux in MRP1-expressing MCF7/VP cells, we found no evidence for glutathione or other conjugates of MX in these cells. Moreover, glutathione depletion with buthionine sulfoximine had no effect on MX transport or sensitivity in MCF7/VP cells. MRP1 substrates are generally amphiphilic anions such as glutathione conjugates or require the presence of physiological levels of glutathione for MRP1-mediated transport. Therefore we conclude that MRP1 overexpression is unlikely to be responsible for increased MX efflux and resistance in MCF7/VP cells. In considering the potential involvement of other MRP family isoforms, a 3-fold increase in the expression of MRP5 was observed in MCF7/VP cells. However, stable expression of a transduced MRP5 expression vector in MCF7/WT cells failed to confer MX resistance. Because other transporters known to be associated with MX resistance, including P-glycoprotein and BCRP/MXR (ABCG2), are not expressed in MCF7/VP cells, we conclude that increased MX efflux and resistance in MCF7/VP cells is attributable to a novel transport mechanism or that MX represents a novel class of cationic, glutathione-independent MRP1 substrates.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
61
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5461-7
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:11454692-ATP-Binding Cassette Transporters, pubmed-meshheading:11454692-Antineoplastic Agents, pubmed-meshheading:11454692-Biological Transport, pubmed-meshheading:11454692-Breast Neoplasms, pubmed-meshheading:11454692-Cell Survival, pubmed-meshheading:11454692-Cyclosporine, pubmed-meshheading:11454692-Drug Resistance, Multiple, pubmed-meshheading:11454692-Drug Resistance, Neoplasm, pubmed-meshheading:11454692-Gene Expression Regulation, Neoplastic, pubmed-meshheading:11454692-Glutathione, pubmed-meshheading:11454692-Humans, pubmed-meshheading:11454692-Mitoxantrone, pubmed-meshheading:11454692-Multidrug Resistance-Associated Proteins, pubmed-meshheading:11454692-RNA, Neoplasm, pubmed-meshheading:11454692-Sulfinpyrazone, pubmed-meshheading:11454692-Time Factors, pubmed-meshheading:11454692-Tumor Cells, Cultured
pubmed:year
2001
pubmed:articleTitle
Resistance to mitoxantrone in multidrug-resistant MCF7 breast cancer cells: evaluation of mitoxantrone transport and the role of multidrug resistance protein family proteins.
pubmed:affiliation
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.