Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines

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dc.contributor.author Mensah-Osman, Edith J. en_US
dc.contributor.author Thomas, Dafydd G. en_US
dc.contributor.author Tabb, Michelle M. en_US
dc.contributor.author Larios, Jose M. en_US
dc.contributor.author Hughes, Dennis P. en_US
dc.contributor.author Giordano, Thomas J. en_US
dc.contributor.author Lizyness, Michelle L. en_US
dc.contributor.author Rae, James M. en_US
dc.contributor.author Blumberg, Bruce en_US
dc.contributor.author Hollenberg, Paul F. en_US
dc.contributor.author Baker, Laurence H. en_US
dc.date.accessioned 2007-09-20T18:08:50Z
dc.date.available 2008-04-03T18:48:40Z en_US
dc.date.issued 2007-03-01 en_US
dc.identifier.citation Mensah-Osman, Edith J.; Thomas, Dafydd G.; Tabb, Michelle M.; Larios, Jose M.; Hughes, Dennis P.; Giordano, Thomas J.; Lizyness, Michelle L.; Rae, James M.; Blumberg, Bruce; Hollenberg, Paul F.; Baker, Laurence H. (2007). "Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines." Cancer 109(5): 957-965. <http://hdl.handle.net/2027.42/55931> en_US
dc.identifier.issn 0008-543X en_US
dc.identifier.issn 1097-0142 en_US
dc.identifier.uri http://hdl.handle.net/2027.42/55931
dc.identifier.uri http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=17279585&dopt=citation en_US
dc.description.abstract BACKGROUND. Approximately 30% to 40% of all patients with osteosarcomas ultimately experience recurrence. The study investigated the hypothesis that the resistance of osteosarcoma to chemotherapy may be related to the expression of a pregnane xenobiotic receptor (PXR) variant protein and its role as the major inducer of P450 3A4 in these tumors. METHODS. Polymerase chain reaction (PCR) and Western blot analysis were used to determine PXR mRNA and protein expression, respectively. Real-time PCR and CYP3A catalytic activity using 7-benzyl-trifluoromethyl coumarin (BFC) as the probe substrate were used to measure the induction of P450 3A4 or MDR1. siRNA transfections were performed for PXR and cytotoxicity determined by a colorimetric based assay or Annexin v-Fitc staining. RESULTS. Differences were observed in the molecular size of the PXR protein expressed in sarcoma cell lines when compared with the wildtype PXR expressed in normal liver, kidney, or small intestine. A polyclonal PXR antibody raised against the N-terminus of the wildtype PXR did not detect PXR expressed in these sarcoma cell lines. In the osteosarcoma cell lines, etoposide and doxorubicin were better inducers of P450 3A4 and MDR1 than rifampin. siRNA against PXR down-regulated P450 3A4 expression only in the osteosarcoma cell line. Cytotoxicity assays showed that the resistance of the osteosarcoma cell lines to etoposide correlated with PXR protein expression levels and activation of P450 3A4 and could be prevented by ketoconazole. CONCLUSION. The results suggest that PXR plays a critical role in the regulation of P450 3A4 expression in osteosarcoma and that its expression and activation in these tumors may influence the effect of chemotherapeutic agents on the induction of target genes implicated in drug resistance. Cancer 2007. © 2007 American Cancer Society. en_US
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dc.publisher Wiley Subscription Services, Inc., A Wiley Company en_US
dc.subject.other Life and Medical Sciences en_US
dc.subject.other Cancer Research, Oncology and Pathology en_US
dc.title Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines en_US
dc.type Article en_US
dc.rights.robots IndexNoFollow en_US
dc.subject.hlbsecondlevel Oncology and Hematology en_US
dc.subject.hlbsecondlevel Public Health en_US
dc.subject.hlbtoplevel Health Sciences en_US
dc.description.peerreviewed Peer Reviewed en_US
dc.contributor.affiliationum Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan ; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan en_US
dc.contributor.affiliationum Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan ; Department of Pathology, University of Michigan, Ann Arbor, Michigan en_US
dc.contributor.affiliationum Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan en_US
dc.contributor.affiliationum Department of Pathology, University of Michigan, Ann Arbor, Michigan en_US
dc.contributor.affiliationum Department of Pathology, University of Michigan, Ann Arbor, Michigan en_US
dc.contributor.affiliationum Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan en_US
dc.contributor.affiliationum Department of Pharmacology, University of Michigan, Ann Arbor, Michigan en_US
dc.contributor.affiliationum Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan ; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan ; Laurence Baker receives grant support from Abbott, Aventis (Sanofi), Lilly, National Institutes of Health, the Robert Urich Foundation, the Hyatt Corporation, and the Walther Foundation. He is on the advisory boards of Ascenta, Hope Foundation, Kanisa, the NCCN Guidelines Committee, and SARC. ; Fax: (734) 998-7118 ; 24 Frank Lloyd Wright Dr., P.O. Box 483, Ann Arbor, MI 48106 en_US
dc.contributor.affiliationother Department of Developmental/Cell Biology, University of California, Irvine, California en_US
dc.contributor.affiliationother Division of Pediatrics, M. D. Anderson Cancer Center, Houston, Texas en_US
dc.contributor.affiliationother Department of Developmental/Cell Biology, University of California, Irvine, California ; Bruce Blumberg is a named inventor on several patents related to SXR: US 6,756,491, US 6,809,178, US 6,984,773. en_US
dc.identifier.pmid 17279585 en_US
dc.description.bitstreamurl http://deepblue.lib.umich.edu/bitstream/2027.42/55931/1/22479_ftp.pdf en_US
dc.identifier.doi http://dx.doi.org/10.1002/cncr.22479 en_US
dc.identifier.source Cancer en_US
dc.owningcollname Interdisciplinary and Peer-Reviewed
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