Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines
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. M. | en_US |
dc.contributor.author | Giordano, Thomas J. | en_US |
dc.contributor.author | Lizyness, Michelle L. | en_US |
dc.contributor.author | Rae, James Michael | 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 | https://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 |
dc.format.extent | 300801 bytes | |
dc.format.extent | 3118 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
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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