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Article: Low-level doxorubicin resistance in benzo[a]pyrene-treated KB-3-1 cells is associated with increased LRP expression and altered subcellular drug distribution

TitleLow-level doxorubicin resistance in benzo[a]pyrene-treated KB-3-1 cells is associated with increased LRP expression and altered subcellular drug distribution
Authors
KeywordsBenzo[a]pyrene
Doxorubicin
Lung-resistance-related protein
Subcellular distribution
Issue Date2000
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/taap
Citation
Toxicology And Applied Pharmacology, 2000, v. 164 n. 2, p. 134-142 How to Cite?
AbstractThe P-glycoprotein (P-gp)-negative epidermoid pharyngeal carcinoma cells KB-3-1 were grown in 0.25 mM benzo[a]pyrene (BaP) for 3 months and increased resistance to doxorubicin, but not to vinblastine, colchicine, or cisplatin, was found. Doxorubicin resistance was not altered by cyclosporin, the P-gp inhibitor. Intracellular accumulation of BaP or calcein, a substrate for P-gp and multidrug resistance protein (MRP), was not altered by inhibitors of the P-gp and MRP. The expression of cytochrome P450 (CYP) 1A1, lung-resistance- related protein (LRP), P-gp, and MRP was investigated. Overexpression of CYP1A and LRP, on the mRNA and protein levels, was found. BaP-treated KB-3-1 cells remained P-gp negative while the level of MRP was not altered. Subcellular accumulation of BaP was found to be localized in the cytoplasm and minimal in the nuclei in BaP treated cells. In contrast, even penetration of BaP to the nuclei and cytoplasm was found in untreated cells. Subcellular distribution of doxorubicin was altered following BaP treatment with localized accumulation of the cancer drug in cytoplasmic organelles but not in the nuclei. Our data suggested that LRP might play a protective role against toxic compounds. The correlation of increased expression of LRP, but not P-gp nor MRP, with decreased doxorubicin accumulation in the nuclear target suggests a pivotal role of this perinuclear transporter in the MDR phenotype of P-gp-negative cancer cells. These results also propose an alternative mechanism of cancer drug resistance emergence, namely, induction of LRP activity following treatment with BaP, an environmental toxicant and a carcinogen. (C) 2000 Academic Press.
Persistent Identifierhttp://hdl.handle.net/10722/92704
ISSN
2015 Impact Factor: 3.847
2015 SCImago Journal Rankings: 1.593
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorCheng, SHen_HK
dc.contributor.authorLam, Wen_HK
dc.contributor.authorLee, ASKen_HK
dc.contributor.authorFung, KPen_HK
dc.contributor.authorWu, RSSen_HK
dc.contributor.authorFong, WFen_HK
dc.date.accessioned2010-09-17T10:54:43Z-
dc.date.available2010-09-17T10:54:43Z-
dc.date.issued2000en_HK
dc.identifier.citationToxicology And Applied Pharmacology, 2000, v. 164 n. 2, p. 134-142en_HK
dc.identifier.issn0041-008Xen_HK
dc.identifier.urihttp://hdl.handle.net/10722/92704-
dc.description.abstractThe P-glycoprotein (P-gp)-negative epidermoid pharyngeal carcinoma cells KB-3-1 were grown in 0.25 mM benzo[a]pyrene (BaP) for 3 months and increased resistance to doxorubicin, but not to vinblastine, colchicine, or cisplatin, was found. Doxorubicin resistance was not altered by cyclosporin, the P-gp inhibitor. Intracellular accumulation of BaP or calcein, a substrate for P-gp and multidrug resistance protein (MRP), was not altered by inhibitors of the P-gp and MRP. The expression of cytochrome P450 (CYP) 1A1, lung-resistance- related protein (LRP), P-gp, and MRP was investigated. Overexpression of CYP1A and LRP, on the mRNA and protein levels, was found. BaP-treated KB-3-1 cells remained P-gp negative while the level of MRP was not altered. Subcellular accumulation of BaP was found to be localized in the cytoplasm and minimal in the nuclei in BaP treated cells. In contrast, even penetration of BaP to the nuclei and cytoplasm was found in untreated cells. Subcellular distribution of doxorubicin was altered following BaP treatment with localized accumulation of the cancer drug in cytoplasmic organelles but not in the nuclei. Our data suggested that LRP might play a protective role against toxic compounds. The correlation of increased expression of LRP, but not P-gp nor MRP, with decreased doxorubicin accumulation in the nuclear target suggests a pivotal role of this perinuclear transporter in the MDR phenotype of P-gp-negative cancer cells. These results also propose an alternative mechanism of cancer drug resistance emergence, namely, induction of LRP activity following treatment with BaP, an environmental toxicant and a carcinogen. (C) 2000 Academic Press.en_HK
dc.languageengen_HK
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/taapen_HK
dc.relation.ispartofToxicology and Applied Pharmacologyen_HK
dc.subjectBenzo[a]pyreneen_HK
dc.subjectDoxorubicinen_HK
dc.subjectLung-resistance-related proteinen_HK
dc.subjectSubcellular distributionen_HK
dc.titleLow-level doxorubicin resistance in benzo[a]pyrene-treated KB-3-1 cells is associated with increased LRP expression and altered subcellular drug distributionen_HK
dc.typeArticleen_HK
dc.identifier.emailWu, RSS: rudolfwu@hku.hken_HK
dc.identifier.authorityWu, RSS=rp01398en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1006/taap.2000.8903en_HK
dc.identifier.pmid10764626-
dc.identifier.scopuseid_2-s2.0-0011036628en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0011036628&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume164en_HK
dc.identifier.issue2en_HK
dc.identifier.spage134en_HK
dc.identifier.epage142en_HK
dc.identifier.isiWOS:000086794000003-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridCheng, SH=7404684691en_HK
dc.identifier.scopusauthoridLam, W=35334620700en_HK
dc.identifier.scopusauthoridLee, ASK=55477304700en_HK
dc.identifier.scopusauthoridFung, KP=7202934739en_HK
dc.identifier.scopusauthoridWu, RSS=7402945079en_HK
dc.identifier.scopusauthoridFong, WF=7102816013en_HK

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