Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The overexpression of the multidrug resistance (mdr1) gene and its product, P-glycoprotein (P-gp), is thought to limit the successful chemotherapy of human tumours. The mechanism by which mdr1 gene and P-gp are overexpressed in human tumours, however, is not yet clear. In this report, we show that the mdm2 (murine double minute 2) gene induced the expression of the mdr1 gene and P-gp in human glioblastoma U87-MG cells, which did not express the MDM2 protein or P-gp. The mdm2 gene, in addition, conferred the resistance of U87-MG cells to the apoptotic cell death induced by etoposide (VP-16) or doxorubicin. Furthermore, treatment with mdm2 antisense oligonucleotides inhibited the expression of P-gp in MDM2-expressing U87-MG cells. These findings suggest that the mdm2 gene may play an important role in the development of MDR phenotype in human tumours.
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PMID:mdm2 gene mediates the expression of mdr1 gene and P-glycoprotein in a human glioblastoma cell line. 888 15

The transcription of MDR1 gene may be increased by mutation or loss of function of p53 gene. In this study, we investigated whether in osteosarcoma, the p53 status is correlated with overexpression of the MDR1 gene product P-glycoprotein. The relationship between P-glycoprotein expression and p53 status was analyzed by immunohistochemistry in 64 primary and 11 metastatic high-grade osteosarcomas. In the same series, we also assessed the nuclear accumulation of MDM2 protein, whose binding to p53 protein provides an alternative mechanism of p53 inactivation. No association was found between mutant-p53 and MDM2 nuclear accumulation either with P-glycoprotein expression or with clinical course. Only increased expression of P-glycoprotein in tumor cells was significantly associated with a poor outcome, further supporting the adverse prognostic value of this marker in osteosarcoma.
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PMID:Relationship between P-glycoprotein expression and p53 status in high-grade osteosarcoma. 991 6

The cytotoxic effects of ecteinascidin-743(ET-743), a novel marine natural product, were evaluated and compared with that of clinically used anticancer agents methotrexate, doxorubicin, etoposide, and paclitaxel in eight human soft tissue sarcoma (STS) cell lines. HT-1080, a fibrosarcoma cell line, and HS-42, a malignant mesodermal cell line, were the most sensitive of the cell lines to methotrexate, doxorubicin, etoposide, and paclitaxel. Other cell lines (IC50s) varied considerably and were more resistant to these agents. ET-743 was more potent than any of these agents, with IC50s in the pM range in all of the cell lines. Cytotoxicity of ET-743 was dose- and time-related (4-72 h exposure). Cytotoxic concentrations of ET-743 produced a S/G2 block in all of the cell lines tested. Three colon adenocarcinoma cell lines, HCT-8, HT-29, and HCT-116, and one breast cancer cell line, MCF-7, were 1-2 logs less sensitive to ET-743 than the STS cell lines. Cell lines were also characterized as to expression of oncogenes and tumor suppressor genes to attempt to correlate sensitivity of these cell lines to ET-743 and other chemotherapeutic agents. All of the cell lines except M8805, a malignant fibrous histiocytoma cell line, had mutations in p53 and/or overexpressed the MDM2 protein. Only HS-18, a liposarcoma cell line, lacked expression of the retinoblastoma protein. None of the cell lines had detectable expression of P-glycoprotein as measured by immunohistochemistry. ET-743 is an extremely potent cytotoxic agent against human STS cell lines and is being evaluated as an antitumor agent in this disease.
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PMID:Sensitivity of soft tissue sarcoma cell lines to chemotherapeutic agents: identification of ecteinascidin-743 as a potent cytotoxic agent. 1155 9

The MDM2 protein is known to be overexpressed in some sarcomas including rhabdomyosarcoma. However, the extent to which the MDM2 protein influences sensitivity to chemotherapeutic drugs is unclear. We have analysed this further using stable transfection of the mdm2 gene into 4 well-characterised human paediatric rhabdomyosarcoma cell lines. Transfection with the mdm2 gene resulted in increased levels of the MDM2 protein in all the cell lines. In 2 of the lines, SCMC and RD, the mdm2 gene caused between 2-fold and 61-fold increase in resistance to vincristine, etoposide and doxorubicin but not to cisplatin. In these lines there was an increase in expression of the mdr-1 gene which encodes P-glycoprotein, but not the mrp1 gene which encodes the multidrug resistance protein (MRP). The resistance was reversible using the MDR modulator PSC833, confirming the presence of P-glycoprotein. We conclude that MDM2 overexpression may be a mechanism by which multidrug resistance is regulated in some rhabdomyosarcomas.
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PMID:High levels of the MDM2 oncogene in paediatric rhabdomyosarcoma cell lines may confer multidrug resistance. 1174 97