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PGP Expression (pgp + expression)
Selected AbstractsExpression of the Multidrug Transporter P-glycoprotein in Brain Capillary Endothelial Cells and Brain Parenchyma of Amygdala-kindled RatsEPILEPSIA, Issue 7 2002Ulrike Seegers Summary: ,Purpose: Based on data from brain biopsy samples of patients with pharmacoresistant partial epilepsy, overexpression of the multidrug transporter P-glycoprotein (PGP) in brain capillary endothelium has recently been proposed as a potential mechanism of resistance to antiepileptic drugs (AEDs). We examined whether PGP is overexpressed in brain regions of amygdala-kindled rats, a widely used model of temporal lobe epilepsy (TLE), which is often resistant to AEDs. Methods: Rats were kindled by stimulation of the basolateral amygdala (BLA); electrode-implanted but nonkindled rats and naive (not implanted) rats served as controls. PGP was determined by immunohistochemistry either 1 or 2 weeks after the last kindled seizure, by using a monoclonal anti-PGP antibody. Six brain regions were examined ipsi- and contralateral to the BLA electrode: the BLA, the hippocampal formation, the piriform cortex, the substantia nigra, the frontal and parietal cortex, and the cerebellum. Results: In both kindled rats and controls, PGP staining was observed mainly in microvessel endothelial cells and, to a much lesser extent, in parenchymal cells. The distribution of PGP expression across brain regions was not homogeneous, but significant differences were found in both the endothelial and parenchymal expression of this protein. In kindled rats, ipsilateral PGP expression tended to be higher than contralateral expression in several brain regions, which was statistically significant in the piriform cortex and parietal cortex. However, compared with controls, no significant overexpression of PGP in capillary endothelial cells or brain parenchyma of kindled rats was seen in any ipsilateral brain region, including the BLA. For comparison with kindled rats, kainate-treated rats were used as positive controls. As reported previously, kainate-induced seizures significantly increased PGP expression in the hippocampus and other limbic brain regions. Conclusions: Amygdala-kindling does not induce any lasting overexpression of PGP in several brain regions previously involved in the kindling process. In view of the many pathophysiologic and pharmacologic similarities between the kindling model and TLE, these data may indicate that PGP overexpression in pharmacoresistant patients with TLE is a result of uncontrolled seizures but not of the processes underlying epilepsy. It remains to be determined whether transient PGP overexpression is present in kindled rats shortly after a seizure, and whether pharmacoresistant subgroups of kindled rats exhibit an increased expression of PGP. Furthermore, other multidrug transporters, such as multidrug resistance,associated protein, might be involved in the resistance of kindled rats to AEDs. [source] Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 1 2005Roisean E. Ferguson Abstract Renal cancer is one of the most chemoresistant tumor types. Using a panel of 10 established renal cancer cell lines that have not been subjected to prior drug selection, the range of functional resistance phenotypes to the tubulin-binding agents paclitaxel, vinblastine, vincristine and patupilone (epothilone B, EPO906) was determined, together with expression of P-glycoprotein (PgP), multidrug resistance associated protein-2 (MRP2) and major vault protein (MVP) proteins. The IC50 values for vincristine correlated positively with PgP expression (r = 0.73; p = 0.031), with values for paclitaxel and vinblastine just failing to reach significance. A significant positive correlation was observed for sensitivity to paclitaxel and MRP2 expression only (r = 0.8; p = 0.013). MVP expression did not correlate with sensitivity to any of the drugs examined. All cell lines exhibited much greater sensitivity to patupilone, demonstrating for the first time the potential use of patupilone in this cancer. In tissue samples from chemotherapy-naive renal cell carcinoma (RCC) patients, marked downregulation or absence of PgP in many tumor cells with expression levels more similar to sensitive cell lines rather than the resistant lines was seen. Similarly, MRP2 was absent or only weakly present in tumor cells, whereas MVP was very strongly upregulated in most tumor samples. This study illustrating discrepancies between results exclusively based on studies in cell lines and findings in vivo suggests that the role of PgP and MRP2 in intrinsic resistance in RCC in vivo may be less than expected from the in vitro findings and supports a potential role for MVP on the basis of in vivo expression studies. © 2004 Wiley-Liss, Inc. [source] Differential regulation of P-glycoprotein genes in primary rat hepatocytes by collagen sandwich and drugsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2002Chow H. Lee Abstract P-glycoprotein (Pgp) is a small family of plasma membrane proteins, which are capable of transporting substrates across cell membranes. Class I and II Pgp are able to transport drugs and have been shown to mediate multidrug resistance (MDR). Class III Pgp is a long chain phospholipid transporter and does not mediate MDR. The regulation of all three Pgp genes is still poorly understood. For instance, it is not clear if the three Pgp genes are co-regulated or differentially regulated by external stimuli. This study examined the effect of drugs and collagen sandwich system on expression and transcription of all the three Pgp genes in primary rat hepatocytes. Consistent with previous findings, dramatic overexpression (25-fold) of Class II Pgp mRNA was seen, upon culturing of hepatocytes onto a single layered collagen gel. Hepatocytes sandwiched between two layers of collagen gel exhibited decreased (4.5-fold) Class II Pgp mRNA expression as compared to the single layer system. Treatment of hepatocytes cultured on the single layer collagen system with cytoskeletal disrupting (cytochalasin D, colchicine) but not cytoskeletal stabilizing (phalloidin, taxol) drugs, suppressed Class II Pgp expression. In all cases, no change in Class II Pgp transcription was observed as demonstrated by nuclear run-on studies. This suggests that collagen configuration and drugs affect Class II Pgp mRNA expression predominantly through post-transcriptional mechanisms. In contrast, parallel increases in mRNA expression and transcription of Class I Pgp gene were observed upon culturing of hepatocytes, in the collagen sandwich system, and treatment with some drugs (cytochalasin D, colchicine, and phalloidin). This suggests that Class I Pgp gene is regulated primarily via transcriptional mechanisms by these stimuli. On the other hand, Class III Pgp gene appears to be post-transcriptionally co-regulated with Class II Pgp gene by treatment with the drugs, while collagen configuration affected both transcription and post-transcription of Class III Pgp gene. Finally, dose-dependent studies using cycloheximide provided further evidence that the two MDR-associated genes are not co-regulated. This study has implications for future studies on the molecular mechanisms of Pgp gene regulation. J. Cell. Biochem. 86: 12,20, 2002. © 2002 Wiley-Liss, Inc. [source] | ||||||||||