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)

Numerous signaling pathways were reported to be involved in the resistance for conventional cytotoxic drugs, although one of the main reasons is the overexpression of P-glycoprotein (P-gp) in multidrug resistant cancer cells. The overexpression of P-gp has been associated with the resistance to a wide range of anticancer drugs. Doxorubicin and paclitaxel are substrates of this transporter system and have an important role for the various human malignancies. In the present study, drug-sensitive MCF7 and multidrug resistant MCF7/ADR (characterized by overexpression of P-gp) human breast cancer cell lines were used as an experimental model. We have found that PS341 and MG132, proteasome inhibitors, reduced the degree of the multidrug resistance (MDR) in MCF7/ADR cells. This phenomenon was accompanied by a decrease in the IC50 value of doxorubicin and paclitaxel from 55.9 +/- 3.46 to 0.60 +/- 0.08 microM, and from 17.61 +/- 1.77 to 0.59 +/- 0.12 microM, respectively. The IC50 values of sensitive cells for doxorubicin and paclitaxel were about 0.42 and 0.83 microM, respectively. The effect of PS341 and MG132 on MCF7/ADR cells was associated with a significant decrease in both protein and gene levels of P-gp expression. Moreover, with regard to the expression of possible signal transduction pathways of mitogen-activated protein kinase (MAPK) related to the activation of mdr1, proteasome inhibitors did significantly influence the activation of these proteins. Western blot analysis revealed that 24 hr exposure of multidrug resistant MCF7/ADR cells with proteasome inhibitors did change the levels of DNA binding activity of nuclear factor-kappaB (NF-kappaB), pERK1/2, c-Jun, and p-c-Jun. In conclusion, we could remark that proteasome inhibitors (especially PS341) attenuate the resistance of MCF7/ADR cells for P-gp substrate drugs of doxorubicin and paclitaxel. Several proteins are supposed to be associated with the resensitization of the cells to conventional cytotoxic drugs, although decreased activity of P-gp is at least involved in the proteasome inhibitor-related resensitization. And influence with MAPK pathways, which have been reported to be associated with the regulation of P-gp, might be contributed to the resensitization brought by proteasome inhibitors.
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PMID:Proteasome inhibitors can alter the signaling pathways and attenuate the P-glycoprotein-mediated multidrug resistance. 1594 97

In the past, people have argued for and against the theory of reciprocal regulation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and P-glycoprotein (Pgp). Data have indicated that this may occur in vitro during drug-induced selection of cells, and in vivo during development. Much of this debate has been caused by a severe lack of mechanistic details involved in such regulation. Our past data indicate that certain Pgp modulators can affect CFTR expression and function. The goal of this study was to investigate the effects of trivalent arsenic (arsenite), a known transcriptional activator of Pgp, on CFTR expression. In vitro analyses in T-84 cells that express basal levels of Pgp and CFTR were conducted using a variety of molecular techniques. Expressions of both genes were altered following treatment with arsenite in a dose- and time-dependent fashion. CFTR expression was suppressed almost three-fold by arsenite, along with a concomitant increase in P-glycoprotein expression. We also report that a member of the MAPK-family, the ERK-mediated signaling cascade is implicated in suppression of CFTR expression following treatment with arsenite. However, this particular pathway is not involved in regulation of P-glycoprotein expression in T-84 cells following treatment with arsenite. Thus, the regulatory pathways that control functional expression of CFTR and P-glycoprotein following arsenite treatment in T-84 cells are distinct and independent.
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PMID:Arsenite regulates Cystic Fibrosis Transmembrane Conductance Regulator and P-glycoprotein: evidence of pathway independence. 1612 Oct 39

During the course of a mechanism-based screening program aimed at identifying new antimitotic agents, a novel microtubule depolymerizing piperazine derivative, 1-(5-chloro-2-methoxybenzoyl)-4-(3-chlorophenyl) piperazine, was identified. The compound, designated CB694, caused inhibition of proliferation of a wide range of cancer cell lines, with an average IC50 of 85 nM. A multidrug-resistant cell line was sensitive to inhibition by CB694, suggesting that this compound is a poor substrate for transport by P-glycoprotein. CB694 caused formation of abnormal mitotic structures in HeLa cells. Specifically, CB694 caused a concentration-dependent increase in bipolar spindles with lagging chromosomes and, with slightly higher concentrations, formation of multipolar mitotic spindles. These mitotic abnormalities occurred at concentrations that did not cause significant changes in the appearance or quantity of interphase microtubules. Coincident with the formation of abnormal mitotic spindles, CB694 caused G2/M arrest. CB694 inhibited the assembly of purified tubulin with an IC50 of 2.3 microM. Colchicine binding was strongly inhibited by CB694, suggesting that it binds to tubulin at the colchicine site. Bcl-2 phosphorylation and activation of ERK and JNK and caspase 3-dependent cleavage of PARP were observed in MDA-MB-435 cells treated with CB694. CB694 caused phosphorylation of Aurora A within 8 hr of treatment, and increases in Aurora A protein levels were coincident with mitotic accumulation. The efficacy of CB694 against a syngeneic murine transplantable solid tumor, Mammary 16/C, was also evaluated. CB694 was well tolerated and showed antitumor activity.
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PMID:CB694, a novel antimitotic with antitumor activities. 1615 90

Active efflux of xenobiotics is a major mechanism of cell adaptation to environmental stress. The ATP-dependent transmembrane transporter P-glycoprotein (Pgp) confers long-term cell survival in the presence of different toxins, including anticancer drugs (this concept is referred to as multidrug resistance, or MDR). The vital importance of this mechanism for cell survival dictates the reliability and promptness of its acquisition. To fulfill this requirement, the MDR1 gene that encodes Pgp in humans must be readily upregulated in cells that express low to null levels of MDR1 mRNA prior to stress. The MDR1 gene and a stable MDR phenotype can be induced after short-term exposure of cells to a variety of cues. This effect is implemented by activation of MDR1 transcription and mRNA stabilization. The MDR1 message abundance is regulated by mechanisms generally involved in stress response, namely activation of phospholipase C, protein kinase C and mitogen-activated protein kinase cascades, mobilization of intracellular Ca2+, and nuclear factor kappa B activation. Furthermore, the proximal MDR1 promoter sites critical for induction are not unique for the MDR1 gene; they are common regulatory elements in eukaryotic promoters. Moreover, MDR1 induction can result from activation of (an) intermediate gene(s) whose product(s), in turn, directly activate(s) the MDR1 promoter and/or cause(s) mRNA stabilization. Redundancy of signal transduction and transcriptional mechanisms is the basis for the virtually ubiquitous inducibility of the MDR1 gene. Thus, the complex network of MDR1 regulation ensures rapid emergence of pleiotropic resistance in cells.
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PMID:Redundancy of biological regulation as the basis of emergence of multidrug resistance. 1616 65

We recently identified two thiazolidin compounds, 5-[(4-methylphenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone (MMPT) and 5-(2,4-dihydroxybenzylidene)-2-(phenylimino)-1,3-thiazolidin (DBPT), that inhibit the growth of human non-small-cell lung and colon cancer cells independent of P-glycoprotein and p53 status. Here we further investigated the mechanism by which these thiazolidin compounds mediate their anticancer effects. Treatment of cancer cells with MMPT and DBPT led to a time-dependent accumulation of cells arrested in the G2/M phase with modulation of the expression of proteins such as cyclin B1, cdc25C, and phosphorylated histone H3. Moreover, treatment with MMPT and DBPT increased M-phase arrest with abnormal spindle formation. DBPT-mediated G2/M phase arrest and phosphorylation of cdc25C and histone H3 were abrogated when JNK activation was blocked either with SP600125, a specific JNK inhibitor, or a dominant-negative JNK1 gene. Moreover, DBPT-mediated microtubule disruption was also blocked by SP600125 treatment. Our results demonstrate that thiazolidin compounds can effectively induce G2/M arrest in cancer cells and that this G2/M arrest requires JNK activation.
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PMID:JNK1-dependent antimitotic activity of thiazolidin compounds in human non-small-cell lung and colon cancer cells. 1617 69

Deoxynivalenol (DON) is a mycotoxin of the trichothecenes family to which human exposure levels can be high. Epidemiological studies suggest a link between DON and gastrointestinal illness. We investigated the interaction of DON with Caco-2 cells, a widely used in vitro model of the human intestinal barrier. The apical to basolateral (absorption) and basolateral to apical (excretion) transports of DON were found strictly proportional to both the initial concentration and the duration of the incubation. The absorption and excretion mean rates were similar to those of mannitol and were increased in the presence of EGTA, a calcium chelator. These data suggest that DON crosses the intestinal mucosa by a paracellular pathway through the tight junctions although some passive transcellular diffusion may not be ruled out. The DON transport was not affected by P-glycoprotein (PgP) or multidrug resistance-associated proteins (MRPs) inhibitors. A prolonged exposure to DON provokes the phosphorylation of the mitogen-activated protein kinases (MAPKs) Erk1/2, p38 and SAPK/JNK, as well as a decrease of the transepithelial resistance, suggesting that DON could trigger intestinal inflammation. These data imply that a chronic exposure to DON contaminated foods may negatively affect human health by altering the intestinal mucosa integrity and by inducing the MAPKs implicated in inflammation.
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PMID:Deoxynivalenol transport across human intestinal Caco-2 cells and its effects on cellular metabolism at realistic intestinal concentrations. 1644 54

Several groups have reported in recent years that members of the plant stress hormones family of jasmonates, and some of their synthetic derivatives, exhibit anti-cancer activity in vitro and in vivo. Jasmonates increased the life span of EL-4 lymphoma-bearing mice, and exhibited selective cytotoxicity towards cancer cells while sparing normal blood lymphocytes, even when the latter were part of a mixed population of leukemic and normal cells drawn from the blood of chronic lymphocytic leukemia (CLL) patients. Jasmonates join a growing number of old and new cancer chemotherapeutic compounds of plant origin. Three mechanisms of action have been proposed to explain the anti-cancer activity of jasmonates. These include: (1) The bio-energetic mechanism-jasmonates induce severe ATP depletion in cancer cells via mitochondrial perturbation; (2) The re-differentiation mechanism-jasmonates induce re-differentiation in human myeloid leukemia cells via mitogen-activated protein kinase (MAPK) activity; (3) The reactive oxygen species (ROS)-mediated mechanism-jasmonates induce apoptosis in lung carcinoma cells via the generation of hydrogen peroxide, and pro-apoptotic proteins of the Bcl-2 family. Several similarities between the effects of jasmonates on plant and cancer cells have been recorded, suggesting that additional analysis of jasmonate effects in plant cells may contribute to a deeper understanding of the anti-cancer actions of these compounds. Those similarities include: induction of cell death, suppression of proliferation and cell cycle arrest, MAPK induction, ROS generation, and enhancement of heat-shock proteins (HSP) expression. Finally, jasmonates can induce death in drug-resistant cells. The drug resistance was conferred by either p53 mutation or P-glycoprotein (P-gp) over-expression. In summary, the jasmonate family of novel anti-cancer agents presents new hope for the development of cancer therapeutics, which should attract further scientific and pharmaceutical interest.
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PMID:Jasmonates in cancer therapy. 1660 Apr 75

The new glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) is cytotoxic toward P-glycoprotein-overexpressing tumor cell lines, i.e. CEM-VBL10, CEM-VBL100, and U-2 OS/DX580. The mechanism of cell death triggered by NBDHEX has been deeply investigated in leukemia cell lines. Kinetic data indicate a similar NBDHEX membrane permeability between multidrug resistance cells and their sensitive counterpart revealing that NBDHEX is not a substrate of the P-glycoprotein export pump. Unexpectedly, this molecule promotes a caspase-dependent apoptosis that is unusual in the P-glycoprotein-overexpressing cells. The primary event of the apoptotic pathway is the dissociation of glutathione S-transferase P1-1 from the complex with c-Jun N-terminal kinase. Interestingly, leukemia MDR1-expressing cells show lower LC50 values and a higher degree of apoptosis and caspase-3 activity than their drug-sensitive counterparts. The increased susceptibility of the multidrug resistance cells toward the NBDHEX action may be related to a lower content of glutathione S-transferase P1-1. Given the low toxicity of NBDHEX in vivo, this compound may represent an attractive basis for the selective treatment of MDR1 P-glycoprotein-positive tumors.
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PMID:A strong glutathione S-transferase inhibitor overcomes the P-glycoprotein-mediated resistance in tumor cells. 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) triggers a caspase-dependent apoptosis in MDR1-expressing leukemia cells. 1676 21

Vaults are evolutionary highly conserved ribonucleoprotein (RNP) particles with a hollow barrel-like structure. They are 41 x 73 nm in size and are composed of multiple copies of three proteins and small untranslated RNA (vRNA). The main component of vaults represents the 110 kDa major vault protein (MVP), whereas the two minor vault proteins comprise the 193 kDa vault poly(ADP-ribose) polymerase (VPARP) and the 240 kDa telomerase-associated protein-1 (TEP1). Vaults are abundantly present in the cytoplasm of eukaryotic cells and they were found to be associated with cytoskeletal elements as well as occasionally with the nuclear envelope. Vaults and MVP have been associated with several cellular processes which are also involved in cancer development like cell motility and differentiation. Due to the over-expression of MVP (also termed lung resistance-related protein or LRP) in several P-glycoprotein (P-gp)-negative chemoresistant cancer cell lines, vaults have been linked to multidrug resistance (MDR). Accordingly, high levels of MVP were found in tissues chronically exposed to xenobiotics. In addition, the expression of MVP correlated with the degree of malignancy in certain cancer types, suggesting a direct involvement in tumor development and/or progression. Based on the finding that MVP binds several phosphatases and kinases including PTEN, SHP-2 as well as Erk, evidence is accumulating that MVP might be involved in the regulation of important cell signalling pathways including the PI3K/Akt and the MAPK pathways. In this review we summarize the current knowledge concerning the vault particle and discuss its possible cellular functions, focusing on the role of vaults in chemotherapy resistance.
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PMID:Cellular functions of vaults and their involvement in multidrug resistance. 1691 21

Overexpression of the MDR1 gene is one of the reasons for multidrug resistance (MDR). Some studies suggested that antioxidants could down-regulate MDR1 expression as a possible cancer treatment. In this report, we try to determine the effects of antioxidants (catalase or N-acetylcysteine [NAC]) on the regulation of intrinsic MDR1 overexpression in HepG2 cells. Adding catalase or N-acetylcysteine to the HepG2 culture led to a significant increase of MDR1 mRNA and P-glycoprotein drug transporter activity. After catalase or NAC treatment, a reduced intracellular reactive oxygen species (ROS) was observed. The JNK inhibitor SP600125 abolished the positive effects of catalase on drug transporter activity in a dose-dependent manner. Furthermore, the up-regulation of P-glycoprotein functions by catalase was only observed in HepG2 cells but not in other cell lines tested (MCF-7, A549, A431). These data suggested that catalase can up-regulate P-glycoprotein expression in HepG2 cells via reducing intracellular ROS, and JNK may mediate this process.
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PMID:Up-regulation of P-glycoprotein expression by catalase via JNK activation in HepG2 cells. 1698 40


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