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)

Nuclear expression of the Y-box-binding protein (YB-1) has been reported to correlate with the expression of P-glycoprotein in breast cancer and osteosarcoma. Overexpression of the ATP-binding cassette (ABC) superfamily, such as P-glycoprotein/multi-drug resistance (MDR) 1 and MDR-associated protein (MRP) 1, 2 and 3, has been reported in various malignant neoplasms. Fifty-four surgically resected synovial sarcomas were examined immunohistochemically for nuclear expression of YB-1 and intrinsic expression of P-glycoprotein, MRP1, MRP2, and topoisomerase II alpha, and the findings were compared with clinicopathological parameters, proliferative activities as evaluated by MIB-1 labelling index (LI), and the patients' prognoses. In addition, MDR1, MRP1, MRP2, and MRP3 mRNA levels were assessed using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method in 22 concordant frozen specimens from these cases and the findings were compared with six control skeletal muscle tissues. Independent prognostic factors were investigated using the Cox proportional hazards regression model. Nuclear expression of YB-1 protein correlated with P-glycoprotein expression (p = 0.0126). Moreover, cases with nuclear expression of YB-1 correlated with poor survival (p = 0.0495) and showed a high topoisomerase II alpha labelling index (topo II alpha LI) (p = 0.0056) and a high MIB-1 LI (p = 0.01). Multivariate Cox analysis showed that only the nuclear expression of YB-1 (p = 0.0136) and high American Joint Committee on Cancer (AJCC) stage (ie stage III or IV) (p < 0.0001) were independent factors for poor prognosis, while the expression of the YB-1 responsive gene products examined was not. These results indicate that the nuclear expression of YB-1 protein is associated with P-glycoprotein expression and proliferative activity as shown by the topo II alpha LI and the MIB-1 LI, and that expression of this protein is an important independent prognostic factor in synovial sarcoma.
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PMID:Nuclear expression of Y-box-binding protein-1 correlates with P-glycoprotein and topoisomerase II alpha expression, and with poor prognosis in synovial sarcoma. 1253 39

To further define the molecular basis for drug resistance to mitoxantrone, a Chinese hamster ovary cell line (MXN(4)) was selected in the presence of 25 nM mitoxantrone and fully characterized. This cell line is 20-fold resistant to mitoxantrone, cross-resistant to several other topoisomerase II poisons, and 2- to 3-fold collaterally sensitive to cisplatin, carboplatin and BCNU. Neither an alteration in cellular uptake of topoisomerase II inhibitor nor overexpression of P-glycoprotein contribute to the drug resistance of MXN(4) cells. Immunoblotting demonstrates equivalent amounts of topoisomerase II alpha and beta in the wild-type and drug resistant cell lines, suggesting that a quantitative alteration in topoisomerase II is not the mechanism of resistance of MXN(4) cells. Mitoxantrone-induced DNA double strand breaks measured in situ were attenuated 28-fold in the drug resistant cell line. Nuclear extracts of MXN(4) cells, as well as topoisomerase II alpha purified to homogeneity from these cells, were found to be markedly resistant to drug-induced covalent DNA: topoisomerase II complex formation. The catalytic activity of purified MXN(4) topoisomerase II was the same as wild-type activity. Thus, the resistance of MXN(4) cells to mitoxantrone involves the expression of a topoisomerase II alpha with altered DNA cleavage activity. The hypersensitivity of this cell line to platinum analogs is due to an apparent increased uptake of these drugs which results in augmented DNA interstrand crosslinking.
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PMID:Characterization of an altered DNA topoisomerase ii-alpha from a mitoxantrone resistant Mammalian-cell line hypersensitive to DNA cross-linking agents. 2155 77


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