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

1. We studied the functional interaction between transport and metabolism by comparing the transport of losartan and its active metabolite EXP 3174 (EXP) across cell monolayers. 2. Epithelial layers of Caco-2 cells as well as MDR1, MRP-1 and MRP-2 overexpressing cells, in comparison to the respective wildtypes, were used to characterize the transcellular transport of losartan and EXP. 3. Losartan transport in MDCK-MDR1 and Caco-2 cells was saturable and energy-dependent with a significantly greater basolateral-to-apical (B/A) than apical-to-basolateral (A/B) flux (ratio=31+/-1 in MDCK-MDR1 and ratio 4+/-1 in Caco-2 cells). The B/A flux of losartan was inhibited by cyclosporine and vinblastine, inhibitors of P-glycoprotein and MRP. In contrast, no active losartan transport was observed in MRP-1 or MRP-2 overexpressing cells. 4. The metabolite was only transported in Caco-2 cells with a B/A-to-A/B ratio of 5+/-1, while lacking active transport in the MDR1, MRP-1 or MRP-2 overexpressing cells. The B/A flux of EXP was significantly inhibited by cyclosporine and vinblastine. 5. In conclusion, losartan is transported by P-glycoprotein and other intestinal transporters, that do not include MRP-1 and MRP-2. In contrast, the carboxylic acid metabolite is not a P-glycoprotein substrate, but displays considerably higher affinity for other transporters than losartan, that again most probably do not include MRP-1 and MRP-2.
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PMID:Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and caco-2 cell monolayers. 1072 73

OC144-093 is a novel substituted diarylimidazole (Mr 495) generated using the OntoBLOCK system, a solid-phase combinatorial chemistry technology, in combination with high-throughput cell-based screening. OC144-093 reversed multidrug resistance (MDR) to doxorubicin, paclitaxel, and vinblastine in human lymphoma, breast, ovarian, uterine, and colorectal carcinoma cell lines expressing P-glycoprotein (P-gp) with an average EC50 of 0.032 microM. Inhibition of MDR by OC144-093 was reversible, but the effect persisted for at least 12 h after removal of compound from the culture medium. OC144-093 had no effect on the response to cytotoxic agents by cells in vitro lacking P-gp expression or expressing a multidrug resistance-associated protein (MRP-1). OC144-093 was not cytotoxic by itself against 15 normal, nontransformed, or tumor cell lines, regardless of P-gp status, with an average cytostatic IC50 of >60 microM. OC144-093 blocked the binding of [3H]azidopine to P-gp and inhibited P-gp ATPase activity. The compound was >50% p.o. bioavailable in rodents and dogs and did not alter the plasma pharmacokinetics of i.v.-administered paclitaxel. OC144-093 increased the life span of doxorubicin-treated mice engrafted with MDR P388 leukemia cells by >100% and significantly enhanced the in vivo antitumor activity of paclitaxel in MDR human breast and colon carcinoma xenograft models, without a significant increase in doxorubicin or paclitaxel toxicity. The results demonstrate that OC144-093 is an orally active, potent, and nontoxic inhibitor of P-gp-mediated multidrug resistance that exhibits all of the desired properties for treatment of P-gp-mediated MDR, as well as for prevention of MDR prior to selection and/or induction of refractory disease.
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PMID:Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. 1085 Apr 44

Human hepatocytes cultured serum-free for up to 6 weeks were used to study expression and induction of enzymes and membrane transport proteins involved in drug metabolism. Phase I drug metabolizing enzymes cytochrome P450 (CYP)1A1, CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4 were detected by Western blot analyses and, when appropriate, by enzymatic assays for ethoxyresorufin-O-deethylase(EROD)-activity and testosterone-6beta-hydroxylase(T6H)-activity. Expression of the membrane transporter multi-drug resistance protein (P-glycoprotein, MDR-1), multidrug resistance-associated protein (MRP-1), and lung-resistance protein (LRP) was maintained during the culture as detected by RT-PCR and Western blot analyses. Model inducers like rifampicin, phenobarbital, or 3-methylcholanthrene and beta-naphtoflavone were able to induce CYP1A or CYP3A4 as well as EROD or T6H activities for up to 30 days. CYP2C9, CYP2C19 and CYP2E1 expression was maintained but not inducible for 48 days. Also, rifampicin and phenobarbital were unable to increase MDR-1 and MRP-1 protein levels significantly.
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PMID:Induction of cytochrome P450 (CYP)1A1, CYP1A2, and CYP3A4 but not of CYP2C9, CYP2C19, multidrug resistance (MDR-1) and multidrug resistance associated protein (MRP-1) by prototypical inducers in human hepatocytes. 1087 7

Sulphoraphane (SF), a naturally occurring isothiocyanate, is a potent anticarcinogen in animal experiments. The mechanism of action of sulphoraphane includes induction of Phase 2 detoxification enzymes, inhibition of carcinogen-activating Phase 1 enzymes, induction of apoptosis and cell cycle arrest, and anti-inflammation. We have recently found that it was accumulated in mammalian cells by up to several hundred-fold over the extracellular concentration, primarily by conjugation with intracellular GSH. The intracellular accumulation levels of SF can reach millimolar concentrations. The anticarcinogenic activity of SF is at least partly dependent on its accumulation levels in cells. Here we show, however, that the accumulated SF was rapidly exported mainly in the form of GSH conjugate (GS-SF) in cultured human cells. It appeared that to sustain the intracellular accumulation levels required a continuous uptake of SF to offset the rapid export of SF/GS-SF. These findings may have important implications for the development of an effective dosing regimen for SF. Moreover, the export was temperature-sensitive and was inhibited by known inhibitors of membrane pumps, suggesting the involvement of such a pump in exporting accumulated SF/GS-SF. Indeed, studies with human leukemia cells (HL60) with or without overexpression of multidrug resistance associated protein-1(MRP-1) and human myeloma cells (8226) with or without overexpression of P-glycoprotein-1 (Pgp-1) indicated that both MRP-1 and Pgp-1 are involved in the export of intracellular SF/GS-SF.
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PMID:High cellular accumulation of sulphoraphane, a dietary anticarcinogen, is followed by rapid transporter-mediated export as a glutathione conjugate. 1198 4

The cytokines IL-6, initially recognized as a regulator of immune and inflammatory response and IL-8, a potential regulator of angiogenesis, also regulate the growth of many tumor cells. Human cancer cells selected for multidrug resistance to common chemotherapeutic agents demonstrate increased expression of IL-6 and IL-8. To determine whether IL-6 or IL-8 overexpression contributes directly to the drug resistant phenotype, IL-6 or IL-8 cDNA were introduced into the paclitaxel sensitive human osteosarcoma cell line U-2OS using the pIRESneo bicistronic expression vector. Interleukin-6 and IL-8 transfectants were selected for either high IL-6 or IL-8 secretion and evaluated in drug resistance assays. Two IL-6 and two IL-8 secreting clones express IL-6 or IL-8 levels of 10 ng/ml and 1 ng/ml in culture, while parental U-2OS and pIRESneo vector transfected control cells express IL-6 and IL-8 levels of 0.005 ng/ml and 0.1 ng/ml, respectively. MTT cytotoxicity with IL-6 transfected cells demonstrates a five-fold increase in resistance to paclitaxel and a four-fold increase in resistance to doxorubicin as compared to U-2OS. There are no changes in mitoxantrone or topotecan resistance in the IL-6 transfectants as compared to parental U-2OS. Northern analysis of IL-6 transfectants demonstrates that the resistant phenotype is not related to increased levels of MDR-1, MRP-1, or LRP. Western analysis also confirms that P-glycoprotein levels are not altered in IL-6 transfectants. Further supporting an MDR-1 independent mechanism of drug resistance, verapamil cannot reverse paclitaxel resistance in transfected cells, findings further supported by rhodamine 123 exclusion data. Treatment of IL-6 transfected cells with paclitaxel, compared with drug-sensitive parental U-2OS, shows U-2OS(IL-6) are significantly more resistant to apoptosis induced by paclitaxel and exhibit decreased proteolytic activation of caspase-3. In contrast U-2OS(IL-8) transfectants demonstrate no appreciable increase in paclitaxel resistance when compared with parental cells. In summary, while both IL-6 and IL-8 are overexpressed in paclitaxel resistant cell lines, only IL-6 has the potential to contribute directly to paclitaxel and doxorubicin resistance in U-2OS. This resistance is through a non-MDR-1 pathway.
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PMID:Overexpression of IL-6 but not IL-8 increases paclitaxel resistance of U-2OS human osteosarcoma cells. 1202 4

Rhabdomyosarcomas generally respond well to chemotherapy, and the residual lesions often are better differentiated than their primaries. This phenomenon may be explained by selective multidrug resistance (MDR) of differentiated tumor cell populations. We assess the role of MDR proteins in chemotherapy-induced differentiation in rhabdomyosarcomas in a clinical setting. Paraffin-embedded samples of 13 pairs of primary untreated rhabdomyosarcomas and their residual, recurrent, or metastatic lesions after chemotherapy were assessed for expression of MDR proteins, including P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP-1), and lung resistance-related protein (LRP). Expression was semiquantitatively scored based on the percentage of isolated immunoreactive tumor cells as follows: 0, negative; 0.5, <5%; 1, 5% to 25%; 2, 26% to 50%; 3, 51% to 75%, and 4, >75%. All specimens after chemotherapy, except the late recurrences, were better differentiated than their primary, untreated specimens. Pgp or MRP-1 expression did not change significantly, but LRP expression increased significantly after chemotherapy. In both untreated and treated samples, LRP was expressed primarily in differentiated cells. The findings indicate that the in vivo expression of LRP, but not of Pgp and MRP-1, is induced by chemotherapeutic treatment in rhabdomyosarcomas. The preferential expression of LRP in differentiated cells and the subsequent more extensive expression after chemotherapy suggests that LRP plays a role in therapy-induced differentiation.
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PMID:Expression of multidrug resistance-associated proteins in rhabdomyosarcomas before and after chemotherapy: the relationship between lung resistance-related protein (LRP) and differentiation. 1261 83

Overexpression of ATP-binding cassette transport proteins, including P-glycoprotein (Pgp), multidrug resistance (MDR) protein (MRP-1), and breast cancer resistance protein (BCRP), is a well-characterized mechanism of MDR in tumor cells. Although the cytotoxic taxanes paclitaxel and docetaxel are substrates for Pgp-mediated efflux, the semisynthetic taxane analogue ortataxel inhibits drug efflux mediated by Pgp as well as, as we recently demonstrated, MRP-1 and BCRP. Nevertheless, ortataxel is not optimal for development as a clinical MDR modulator because of its cytotoxicity [corrected]. We sought to identify noncytotoxic taxane-based broad-spectrum modulators from a library of noncytotoxic taxane-based reversal agents (tRAs) designed by eliminating the C-13 side chain of the taxane molecule, which inhibits microtubule depolymerization. Twenty tRAs, selected based on modulation of paclitaxel cytotoxicity in Pgp-overexpressing MDA435/LCC6(mdr1) cells, were studied for modulation of retention and cytotoxicity of substrates of MRP-1 and BCRP as well as Pgp in established cell lines overexpressing each of these transporters. Four tRAs modulated MRP-1 and 17 modulated BCRP in addition to Pgp. The four broad-spectrum tRAs strongly modulated daunorubicin and mitoxantrone efflux and enhanced their cytotoxicity in cell lines overexpressing the three MDRs, decreasing IC(50) values by as much as 97% [corrected]. These tRAs, especially tRA 98006, have promise for development as clinical broad-spectrum MDR modulators and warrant more preclinical analysis to determine pharmacokinetic interactions and efficacy.
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PMID:Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. 1461 93

Understanding and overcoming multidrug resistance (MDR) may be a promising strategy to develop more effective pharmacotherapies for malignant gliomas. In the present study, human malignant glioma cell lines (n=12) exhibited heterogeneous mRNA and protein expression and functional activity of the mdr gene-encoded P-glycoprotein (PGP) and MDR-associated protein (MRP). Correlation between mRNA expression, protein levels and functional activity was strong. Inhibition of PGP activity by verapamil or PSC 833 enhanced the cytotoxic effects of vincristine, doxorubicin, teniposide and taxol. Inhibition of MRP activity by indomethacin or probenecid enhanced the cytotoxic effects of vincristine, doxorubicin and teniposide. The human cerebral endothelial cell line, SV-HCEC, exhibited the strongest PGP activity of all cell lines. Five primary human glioblastomas and one anaplastic astrocytoma displayed heterogenous protein levels of PGP and MRP-1 in tumor cells and of PGP in biopsy specimens in vivo, but no functional activity of these proteins upon ex vivo culturing. These data suggest that the glioma cell line-associated MDR-type drug resistance is a result of long-term culturing and that cerebral endothelial, but not glioma cells, may contribute to MDR-type drug resistance of gliomas in vivo.
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PMID:P-glycoprotein and multidrug resistance-associated protein mediate specific patterns of multidrug resistance in malignant glioma cell lines, but not in primary glioma cells. 1465 54

Drug resistance to cisplatin (CDDP) would represent a major obstacle for cancer therapy. The adenosine triphosphate (ATP) binding cassette (ABC) family of transport proteins, such as the 170 kDa P-glycoprotein (multidrug resistance gene-1; MDR-1) and the 190 kDa multidrug resistance-associated proteins (MRPs), are associated with multidrug resistance, including resistance to CDDP. The purpose of the present study was to investigate the relationship between cyclooxygenase-2 (COX-2) expression and the level of chemosensitivity to CDDP. We established the COX-2-overexpressed colon cancer cell line TR-5 from HCT-15 cells. We quantified the expression of m-RNA for MRP-1 and MDR-1 by a real-time PCR method, determining that the values of each gene/standardized GAPDH in HCT-15 and TR-5 were 23+/-0.4 and 6.1+/-0.5 in MRP-1 (p<0.02) and 9.0+/-4.8 and 3.6+/-0.5 in MDR-1, respectively. With respect to chemosensitivity, survival rates for 3 microg/ml and 10 microg/ml of CDDP were 81.5+/-12.2% and 26.1+/-11.7% (IC50=6.5 microg/ml) for HCT-15 and 96.6+/-1.7% and 77.4+/-4.9% (IC50=18.5 microg/ml) for TR-5, respectively, thus TR-5 showed higher resistance to CDDP than HCT-15 did with statistical differences. We also demonstrated a successful re-sensitization to CDDP toxicity in TR-5 by means of the COX-2 selective inhibitor JTE-522, 4-(4-cyclohexyl-2-methyl-1, 3-oxazol-5-yl)-2-fluorobenzene sulfonamide, which markedly decreased the IC50 of CDDP for TR-5 (from 17.3+/-2.6 microg/ml to 8.6+/-2.5 microg/ml). In conclusion, COX-2 overexpression induced increased MRP-1 expression in a colon cancer cell line, TR-5, resulting in chemoresistance to CDDP that was approximately triple the level of chemoresistance observed in the original HCT-15 cells line, as measured by calculation of the IC50. We also confirmed the efficacy of pretreatment of TR-5 cells with the COX-2 selective inhibitor JTE-522 in restoring chemosensitivity of these cells to CDDP, suggesting a strategy for overcoming drug resistance to CDDP.
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PMID:Cyclooxygenase-2 gene induction causes CDDP resistance in colon cancer cell line, HCT-15. 1551 78

Aplidin-resistant IGROV-1/APL cells were derived from the human ovarian cancer IGROV-1 cell line by exposing the cells to increasing concentration of Aplidin for eight months, starting from a concentration of 10 nM to a final concentration of 4 microM. IGROV-1/APL cell line possesses five fold relative resistance to Aplidin. IGROV-1/APL resistant cell line shows the typical MDR phenotype: (1) increased expression of membrane-associated P-glycoprotein, (2) cross-resistance to drugs like etoposide, doxorubicin, vinblastine, vincristine, taxol, colchicin and the novel anticancer drug Yondelis (ET-743). The Pgp inhibitor cyclosporin-A restored the sensitivity of IGROV-1/APL cells to Aplidin by increasing the drug intracellular concentration. The resistance to Aplidin was not due to the other proteins, such as LPR-1 and MRP-1, being expressed at the same level in resistant and parental cell line. The finding that cells over-expressing Pgp are resistant to Aplidin was confirmed in CEM/VLB 100 cells, that was found to be 5-fold resistant to Aplidin compared to the CEM parental cell line.
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PMID:Induction of resistance to Aplidin in a human ovarian cancer cell line related to MDR expression. 1625 64


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