Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many plant-derived isothiocyanates (ITCs), which occur in human diet, are potent cancer chemopreventive agents in animals. Among the anticarcinogenic mechanisms that have been revealed for ITCs is the inhibition of cell proliferation. We report that exposure of cancer cells to either allyl-ITC (AITC), benzyl-ITC (BITC), or phenethyl-ITC (PEITC) for only 3 h was long enough for the inhibition of cell growth, based on a comparison of IC50 values; regardless of the origin of cancer cells; and even in drug-resistant cells that overexpressed multidrug resistance associated protein-1 (MRP-1) or P-glycoprotein-1 (Pgp-1). In contrast, the inhibitory effect of another ITC, sulforaphane (SF), on these cells was highly time dependent. The finding that some ITCs could inhibit the proliferation of cancer cells in a largely time-independent manner is significant because ITCs that enter the human body are rapidly cleared through urinary excretion. Using human promyelocytic leukemia HL60/S as model cells, and focusing on AITC and BITC, we found that these ITCs modulated multiple cellular targets involved in proliferation, including the disruption of mitochondrial membrane potential, activation of multiple caspases, arrest of cell cycle progression, and induction of differentiation. Again, only a 3-h incubation of the cells with the ITCs was enough to exert their full effect on these targets. Taken together, our findings suggest that selected ITCs can rapidly initiate growth inhibition of cancer cells by simultaneously modulating multiple cellular targets, and their antiproliferative activity may be largely unaffected by their metabolism and disposition in vivo.
...
PMID:Selected isothiocyanates rapidly induce growth inhibition of cancer cells. 1457 69

Major determinants of the bioavailability of drugs are the degree of intestinal absorption and the hepatic first-pass effect. Drugs need to overcome several membrane barriers before reaching the systemic circulation, each of which expresses an array of specialized transport proteins for drug uptake or efflux. The P-glycoprotein MDR1 (multidrug resistance gene product, ABCB1) is expressed at the apical surface of enterocytes, where it mediates the efflux of xenobiotics into the intestinal lumen before these can access the portal circulation. Increased expression of MDR1 reduces the bioavailability of MDR1 substrates such as digoxin, cyclosporin, and taxol. Numerous xenobiotics can induce the MDR1 gene through activation of the nuclear pregnane X receptor (PXR). This explains the risk for drug interactions that is inherent to pharmacotherapy with PXR ligands such as rifampin, phenobarbital, statins, and St. John's wort. Other PXR-regulated genes include cytochrome P450 3A4, the digoxin and bile salt transporter Oatp2 (organic anion transporting polypeptide 2, Slc01a4) of the basolateral hepatocyte membrane, and the xenobiotic efflux pump Mrp2 (multidrug resistance associated protein 2, Abcc2) of the canalicular hepatocyte membrane. A second orphan nuclear receptor that is activated by xenobiotics is the constitutive androstane receptor (CAR), which induces Mrp2 and Mrp3 (Abcc3). The PXR and CAR are thus important "xenosensors" that mediate drug-induced activation of the detoxifying transport and enzyme systems in liver and intestine.
...
PMID:Regulation of drug and bile salt transporters in liver and intestine. 1470 63

Multidrug resistance, cross-resistance to structurally and functionally unrelated drugs, is an important cause of treatment failure in acute leukemia. Multidrug resistance can result from the overexpression of ATP-dependent efflux pumps, such as P-glycoprotein and members of the multidrug resistance associated protein (MRP) family. Recently a novel transporter has been identified, which is called breast cancer resistance protein (BCRP), ABCG2 or mitoxantrone resistance protein. BCRP confers resistance to chemotherapeutic agents, such as mitoxantrone, doxorubicin and daunorubicin. This review describes BCRP detection techniques and the normal physiology of BCRP. The role of BCRP in the physiology of hematopoietic stem cells is addressed as well as the involvement of BCRP in multidrug resistance in acute leukemia. In AML and ALL, several studies showed that BCRP is expressed and functionally active at low, but variable levels. However, further studies are warranted to investigate its effect on clinical outcome, and explore whether patients could benefit from the combination of BCRP inhibitors and chemotherapy.
...
PMID:Breast cancer resistance protein (BCRP) in acute leukemia. 1516 Sep 35

In our previous work, cellular prion protein (PrPc) was identified as an upregulated gene in adriamycin-resistant gastric carcinoma cell line SGC7901/ADR compared to its parental cell line SGC7901. Here we investigate the expression of PrPc in gastric cancer and whether it was involved in multidrug resistance (MDR) of gastric cancer. We demonstrated that PrPc was ubiquitously expressed in gastric cancer cell lines and tissues. PrPc conferred resistance of both P-glycoprotein (P-gp)-related and P-gp-nonrelated drugs on SGC7901, which was accompanied by decreased accumulation and increased releasing amount of adriamycin in PrPc-overexpressing cell line. Inhibition of PrPc expression by antisense or RNAi technology could partially reverse multidrug-resistant phenotype of SGC7901/ADR. PrPc significantly upregulated the expression of the classical MDR-related molecule P-gp but not multidrug resistance associated protein and glutathione S-transferase pi. The PrPc-induced MDR could be partially reversed by P-gp inhibitor verapamil. PrPc could also suppress adriamycin-induced apoptosis and alter the expression of Bcl-2 and Bax, which might be another pathway contributing to PrPc-related MDR. The further study of the biological functions of PrPc may be helpful for understanding the mechanisms of occurrence and development of clinical gastric carcinoma and PrPc-related MDR and developing possible strategies to treat gastric cancer.
...
PMID:Overexpression and significance of prion protein in gastric cancer and multidrug-resistant gastric carcinoma cell line SGC7901/ADR. 1538 5

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 IC(50) 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.
...
PMID:Intrinsic chemotherapy resistance to the tubulin-binding antimitotic agents in renal cell carcinoma. 1564 38

This study was carried out to explore whether efflux-mediated and saturable mechanisms play any role toward poor and variable intestinal absorption of rifampicin. In situ segmental permeability of rifampicin at various residence times was determined in rat gastrointestinal tract using the ligated loop technique. The involvement of efflux-mediated and saturable absorption of rifampicin was studied in rat intestine using the everted sac method. The samples were analyzed by a validated HPLC method. Rifampicin showed decreased permeability in jejunum and ileum with an increase in residence time. The permeation of rifampicin from the serosal to the mucosal side (secretion) was significantly higher than permeation from the mucosal to the serosal side (absorption) of jejunum and ileum. This indicated the involvement of efflux-mediated transport. Addition of verapamil, an inhibitor for P-glycoprotein (Pgp), multidrug resistance associated protein-2 (MRP-2), and other related transporters, increased absorption of rifampicin in jejunum and ileum by 2-3-fold and decreased secretion by almost 4-fold. The permeation rate (flux) of rifampicin through duodenum increased with concentration up to 300 microg/mL, becoming constant thereafter, indicating the existence of saturable absorption. There was no saturable permeation in jejunum and ileum. Thus the present study indicates the involvement of efflux-mediated and saturable absorption mechanisms of rifampicin in rat intestine, which act as barriers to the absorption of the drug. This explains the drug's poor absolute bioavailability. As Pgp varies from person to person to an extent of 2-8-fold, it can be one direct reason for the interindividual variable bioavailability shown by rifampicin.
...
PMID:Evidence of efflux-mediated and saturable absorption of rifampicin in rat intestine using the ligated loop and everted gut sac techniques. 1602 6

One of the major problems related with anticancer chemotherapy is resistance against anticancer drugs. The ATP-binding cassette (ABC) transporters are a family of transporter proteins that are responsible for drug resistance and a low bioavailability of drugs by pumping a variety of drugs out cells at the expense of ATP hydrolysis. One strategy for reversal of the resistance of tumor cells expressing ABC transporters is combined use of anticancer drugs with chemosensitizers. In this review, the physiological functions and structures of ABC transporters, and the development of chemosensitizers are described focusing on well-known proteins including P-glycoprotein, multidrug resistance associated protein, and breast cancer resistance protein.
...
PMID:ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. 1620 68

The interaction of moxidectin (a macrocyclic lactone, ML) with P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs) and breast cancer resistance protein (BCRP) was studied in primary cultures of rat hepatocytes by measuring the intracellular accumulation of [14C]-moxidectin over 72 h in the presence of specific inhibitors: for P-gp, verapamil (10 microM); for MRPs, MK571 (100 microM), indomethacin (10 microM) and probenecid (3.8 mM); and for BCRP, fumitremorgin C (5 microM). The P-gp and MRP inhibitors increased significantly (P < 0.01) by 48.7%, 49.8%, 49.9% and 57.2% the area under the time-intracellular concentration curve (AUC) of moxidectin in rat hepatocytes, while the BCRP inhibitor, fumitremorgin C, had no effect on the AUC compared with the control. In addition, the mRNAs of all the drug transporters studied were detected in rat hepatocytes from 0 to 72 h. Using this cellular model it has been shown that MRP inhibitors increase moxidectin intracellular concentrations to a similar extent as the P-gp inhibitor. The identification of all the transporters that interact with MLs remains a challenge, which currently concerns several important therapeutic fields.
...
PMID:The interaction between moxidectin and MDR transporters in primary cultures of rat hepatocytes. 1651 64

Multidrug resistance of neoplastic tissue is often associated with the overexpression and increased drug transport activity of plasma membrane transporters like P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs) or breast cancer resistance protein, as well as with the elevation of the glutathione detoxification pathway. We have already described the overexpression of P-gp under the selection pressure of vincristine in L1210 mouse leukemia cells. In the present study, mechanisms of multidrug resistance induced in L1210 cells cultivated in the presence of doxorubicin were analyzed. The selection pressure of both vincristine (yielding a resistant subline of L1210 cells, R(V)) and doxorubicin (yielding a resistant subline of L1210 cells, R(D)) induced a dramatic depression of cell sensitivity to both drugs. Both R(V) and R(D) cells demonstrated a lack of ability to accumulate calcein/AM and fluo-3/AM as fluorescent substrates of P-gp and MRP. The retention of dyes could be reached in both cell sublines by the application of inhibitors of P-gp (like verapamil) but not by probenecid - an inhibitor of anion transporters, including MRPs. Massive protein bands, at a M(r) range of 130-180 kDa that interact with c219 antibody against P-gp, were detected in the crude membrane fraction isolated from both R(V) and R(D) (but not from L1210) cells by Western blot. The cytosolic activity of glutathione S-transferase was found to be similar in R(V) and R(D) cells and did not differ significantly from the activity ascertained in parental L1210 cells. Neither the R(V) nor R(D) cell sublines differed considerably, as measured by cell ultrastructure. In conclusion, based on P-gp overexpression, both doxorubicin and vincristine induce a common multidrug resistance phenotype in L1210 cells.
...
PMID:L1210 cells cultivated under the selection pressure of doxorubicin or vincristine express common mechanisms of multidrug resistance based on the overexpression of P-glycoprotein. 1696 37

Cornea is considered as a major barrier for ocular drug delivery. Low ocular bioavailability of drugs has been attributed primarily to low permeability across corneal epithelium, thus leading to sub-therapeutic concentrations of drug in the eye and treatment failure. The role of drug efflux proteins, particularly the P-glycoprotein (P-gp) in ocular drug bioavailability has been reported. The objective of this research was to determine whether human corneal epithelium expresses multidrug resistance associated proteins (MRPs) contributing to drug efflux by employing both cultured corneal cells and freshly excised rabbit cornea. SV40-HCEC and rPCEC were selected for in vitro testing. SV40-HCEC and freshly excised rabbit corneas were utilized for transport studies. [(3)H]-cyclosporine-A and [(14)C]-erythromycin, which are known substrates for ABCC2 and MK-571, a specific inhibitor for MRP were applied in this study. RT-PCR indicated a unique and distinct band at approximately 272 bp corresponding to ABCC2 in HCEC, SV40-HCEC, rabbit cornea, rPCEC, and MDCKII-MRP2 cells. Also RT-PCR indicated a unique band approximately 181 bp for HCEC and SV40-HCEC. Immunoprecipitation followed by Western Blot analysis revealed a specific band at approximately 190 kDa in membrane fraction of SV40-HCEC, MDCKII-MRP2 and no band with isotype control. Uptake of [(3)H]-cyclosporine-A and [(14)C]-erythromycin in the presence of MK-571 was significantly enhanced than control in both SV40-HCEC and rPCEC. Similarly a significant elevation in (A-->B) permeability of [(3)H]-cyclosporine-A and [(14)C]-erythromycin was observed in the presence of MK-571 in SV40-HCEC. A-->B transport of [(3)H]-cyclosporine-A was elevated in the presence of MK-571 in freshly excised rabbit cornea indicating potential role of this efflux transporter and high clinical significance of this finding.
...
PMID:Molecular evidence and functional expression of a novel drug efflux pump (ABCC2) in human corneal epithelium and rabbit cornea and its role in ocular drug efflux. 1715 53


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---