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 multidrug transporting cell membrane molecule P-glycoprotein can be spontaneously expressed in human glioma cells. Transcripts of mdr genes were detected in glial tumor cells by polymerase chain reaction and Northern blotting, expression of P-glycoprotein was analyzed by immunocytochemistry and functional activity by cytofluorometry of fluorescent probe transport. In vitro treatment of glioma cells with vincristine induced coordinate over-expression of both mdr1 and mdr3 genes associated with very high P-glycoprotein-mediated multidrug transport, resistant to the inhibitory activity of chemosensitizers like verapamil. The physiological modulators of multidrug transport are as yet unknown. We therefore initiated a screening program to analyze the effects of cytokines on multidrug transport. We observed, that transforming growth factors (TGF)-beta 1, -beta 2, and -beta 1.2-but not the related bone morphogenetic protein (BMP) 2--inhibited multidrug transport. Interestingly, BMP 2 antagonized the TGF-beta induced inhibition of multidrug transport.
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PMID:Spontaneous multidrug transport in human glioma cells is regulated by transforming growth factors type beta. 167 77

Solitary stroma-invading tumor cells expressing the ATP-binding cassette transporter P-glycoprotein have been reported to be associated with a significantly higher incidence of vessel invasion and lymph node metastases. In contrast to P-gp-mediated multidrug resistance (MDR) which has become well characterized over the last decade, little is known about further morphological and functional alterations in drug-resistant tumor cells. Binding of malignant cells to components of the extracellular matrix mediated by beta 1 integrins has been suggested to play a substantial role in the metastatic cascade. We studied alterations of beta 1 integrin expression and in vitro adhesiveness to extracellular matrix proteins of the human renal carcinoma line Caki-1 in comparison to the vinblastine resistant sublines Caki-1/V1 and Caki-1/V10 (cultured in the presence of 1 ng/ml and 10 ng/ml vinblastine, respectively). Both VLA-1 and VLA-2 receptors were acquired by the Caki-1/V10 subline, whereas untreated and Caki-1/VI cells lacked surface expression of these antigens. VLA-6 was found to be decreased in the vinblastine-resistant sublines. Attachment of drug-resistant Caki-1/V1 and Caki-1/V10 cells to collagen type I was significantly increased when compared to parental cells (p < or = 0.005). Significant differences in the attachment to type IV collagen were observed between Caki-1/V10 and untreated cells (p < or = 0.045). Both Caki-1/V1 and Caki-1/ V10 cells exhibited increased adhesion to fibronectin when compared to cells of the untreated line (p < or = 0.04). Whether an aberrant expression of beta 1 integrin receptors in resistant cells in combination with altered tumor cell adhesiveness is caused by MDR induction or whether it is an epiphenomenon of cytotoxic stress is unknown. Future studies will be needed to characterize the clinical relevance of MDR-associated changes in tumor cells.
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PMID:Exposure to vinblastine modulates beta 1 integrin expression and in vitro binding to extracellular matrix molecules in a human renal carcinoma cell line. 903 Feb 41

Resistance to antimitotic agents is caused by decreased accumulation, altered tubulin, altered microtubule-associated proteins and increased metabolism. Vinca alkaloids, paclitaxel and docetaxel are actively effluxed by P-glycoprotein and/or the MRP1. Decreased intracellular accumulation is one of the major determinants of resistance to antimitotic agents. Increased tubulin levels and a decreased polymerization ratio were observed in resistant cells. Increased acetylation of tubulin and altered intracellular distribution of tubulin were also observed in resistant cells; however, the relationship between the function of tubulin and resistance remains unclear. The expression of each beta-tubulin isotype (beta 1-beta 6) is altered in resistant cells, but the functional differences among the isotypes have not been clarified. Recent evidence has demonstrated the alteration of binding properties of antimitotic agents in resistant cells. Therefore, the altered expressions of tubulin isotypes and related molecules might influence the antimitotic action and adverse events by antimitotic agents. Taxanes are metabolized and inactivated by p450 isozymes, and this is related to drug-resistant to taxanes.
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PMID:Cytoskeletons and antimitotic agents developed in Japan. 1040 40

Expression of P-glycoprotein (P-gp) mediated multidrug resistance (MDR) has been suggested to be associated with an impaired clinical outcome in several malignancies. In contrast to P-gp itself, further phenotypical and functional alterations related to MDR are poorly characterized. In this in vitro study, we analyzed two Burkitt's lymphoma cell lines (Raji and Daudi) for the beta 1 integrin phenotype prior to and after induction of MDR via co-cultivation with vincristine. A significant loss of the VLA-3 (CD49c/CD29) adhesion receptor was observed whereas all other intergins analyzed lacked considerable changes. We conclude that induction of P-gp mediated MDR does not only affect resistance to cytotoxic drugs but also induces cellular changes with potential relevance for migratory and/or adhesive properties of malignant cells.
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PMID:Loss of VLA-3 (CD49c/CD29) expression in two multidrug resistant Burkitt's lymphoma cell lines. 1085 27