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

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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)

Vesicular neurotransmitter transporters function in synaptic vesicles and other subcellular organelles and they were thought to be involved only in neurotransmitter storage. Several findings have led us to test novel aspects of their function. Cells expressing a c-DNA coding for one of the rat monoamine transporters (VMAT1) become resistant to the neurotoxin N-methyl-4-phenylpyridinium (MPP+) [Liu et al. (1992) Cell, 70, 539-551]. The basis of the resistance is the VMAT1-mediated transport and sequestration of the toxin into subcellular compartments. In addition, the deduced sequence of VMAT1 predicts a protein that shows a distinct homology to a class of bacterial drug resistance transporters (TEXANs) that share some substrates with mammalian multidrug resistance transporters (MDR) such as the P-glycoprotein. These findings induced us to test whether compounds that are typically transported by MDR interact also with vesicular transporters. The use of [3H]reserpine binding to determine drug interactions with VMAT allowed assessment of the ability of various drugs to bind to the substrate site of the transporter. Cytotoxic compounds such as ethidium, isometamidium, tetraphenylphosphonium, rhodamine, tacrine and doxorubicin, interact specifically with vesicular monoamine transporters. Verapamil, a calcium channel blocker, is also a competitive inhibitor of transport. In the case of rhodamine, fluorescence measurements in digitonin-permeabilized cells demonstrated ATP-dependent VMAT-mediated transport. The results imply that even though the bacterial and vesicular transporters are structurally different from the P-glycoprotein, they share a similar substrate range. These findings suggest a novel possible way of protection from the effects of toxic compounds by removal to subcellular compartments.
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PMID:The pharmacological profile of the vesicular monoamine transporter resembles that of multidrug transporters. 854 51

1. Little information is available about the pharmacokinetic interactions of anticancer drugs in man. However, clinically significant drug interactions do occur in cancer chemotherapy, and it is likely that important interactions have not been recognized. 2. Specific cytochrome P450 (CYP) enzymes have been recently shown to be involved in the metabolism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer drugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide could be activated in tumour tissues containing this enzyme. 3. As examples of recently found, clinically significant interactions, cyclosporin considerably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhibitors inhibit P-glycoprotein mediated drug elimination. 4. Appropriate caution should be exercised when combining P-glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy.
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PMID:The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions. 870 57

A series of 36 purine and purine analog derivatives have been synthesized and tested for their ability to modulate multidrug resistance in vitro (P388/VCR-20 and KB-A1 cells) and in vivo (P388/VCR leukemia). Compounds were compared to S9788, a triazine derivative which has already shown some activity during phase 1 clinical trials and also a limiting cardiovascular side effect possibly linked to its calcium channel affinity. The fact that active compounds increase adriamycin accumulation in the resistant KB-A1 cells, and not in the sensitive KB-3-1 cells, suggests they act predominantly by inhibiting the P-glycoprotein-catalyzed efflux of cytotoxic agents. No direct relation was found between the affinity for the phenylalkylamine binding site of the calcium channel and in vitro sensitization of resistant cells. In vivo, when administered po in association with vincristine (0.25 mg/kg), five compounds (3, 4, 9, 25, and 26), of very differing calcium channel affinities (Ki from 5 to 560 nM), fully restored (T/V > or = 1.4) the sensitivity of P388/VCR leukemia to vincristine.
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PMID:New purines and purine analogs as modulators of multidrug resistance. 883 75

Agents that inhibit P-glycoprotein may restore sensitivity to some antitumor drugs in cancer patients. Optimization of the specificity and potency of one class of chemosensitizing agents related to verapamil has led to the identification of alpha-(3,4-dimethyoxyphenyl)-3,4-dihydro-6, 7-dimethoxy-alpha-[(4-methylphenyl) thio]-2(1H)-isoquinolineheptanenitrile, designated CL 329,753. In vitro, 0.1 to 2.0 microM CL 329,753 restored sensitivity to drugs in the multidrug resistance (MDR) phenotype in cell lines that overexpress P-glycoprotein. CL 329,753 was greater than 10-fold more potent and efficacious than cyclosporine A or verapamil in vitro, particularly in cells that express high levels of P-glycoprotein. The enhanced activity of CL 329,753 may be related to its inability to be transported by P-glycoprotein, since low drug accumulation of cyclosporine or verapamil but not CL 329,753 was found in P-glycoprotein-containing cells, yet all three agents inhibited vinblastine binding to membranes containing P-glycoprotein and inhibited photoaffinity labeling of P-glycoprotein. In vivo, CL 329,753 resensitized drug-resistant tumors to vinblastine or doxorubicin in an ascitic or solid tumor model, respectively. No alteration in the plasma pharmacokinetic profile of doxorubicin by CL 329,753 has been found. Furthermore, the compound had 70-fold less calcium channel antagonistic activity compared with verapamil.
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PMID:alpha-(3,4-dimethyoxyphenyl)-3,4-dihydro-6,7-dimethoxy-alpha- [(4-methylphenyl)thio]-2(1H)-isoquinolineheptanenitrile (CL 329,753): a novel chemosensitizing agent for P-glycoprotein-mediated resistance with improved biological properties compared with verapamil and cyclosporine A. 888 13

P-glycoprotein plays a key role in the mechanisms of multidrug resistance in experimental tumors as well as in clinical tumors in acquired-type resistance and in intrinsic-type resistance. Thus the therapeutic approaches targeting the P-glycoprotein would provide benefits in eradication of drug-resistant tumor cells. Practical approaches to overcoming of multidrug resistance by targeting the P-glycoprotein would be; to use agents including calcium channel blocker-related agents and membrane-modifying agents that interact with P-glycoprotein, although some potential problems concerning side effects still remained to be studied.
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PMID:[Overcoming of multidrug resistance and its clinical application]. 915 61

Structure/functional studies previously reported showed that in a series of simple organic cations in which the charge is delocalized, an aromatic ring and a minimal degree of lipophilicity (log P > -1) were required for recognition by murine cells which express P-glycoprotein (p-gp)-mediated multidrug resistance (MDR). In the present report we find that 3H-octylpyridinium, the simple aromatic cation which has been shown to be preferentially toxic to MDR- as compared to MDR+ cells, accumulates 4.7-fold greater in the MDR- cell line. In contrast, we find that 3H-guanidinium which displays no selective toxicity between MDR+ and MDR- cells, shows no significant uptake differences between these two cell types. We also present data which demonstrate that other organic cations which contain aromatic rings, a minimal degree of lipophilicity (log P> -1) and carry a delocalized (Rho 123) or shielded (triphenylmethyl phosphonium) positive charge, also accumulate to a greater degree in MDR- vs MDR+ cells. Additionally, we find that human cells which express p-gp MDR, have similar requirements for recognition of these simple compounds. In fact, the sensitivity profiles of these compounds closely correlate between murine and human cell lines. It was also found that none of the series of simple organic compounds tested showed modulatory activity in MDR+ cells, as assayed by monitoring retention of Rho 123. Thus, the requirements for MDR recognition vs those for MDR modulation are clearly distinguished with these simple structured compounds. In comparison, the calcium channel antagonist, verapamil, and a calcium channel agonist, Bay K 8644, both showed modulatory activity by increasing Rho 123 retention in MDR+ cells, further supporting the interpretation that verapamil's modulation of MDR is unrelated to its action on calcium flux. Overall, the data presented here add further information for defining the structural requirements of compounds for their recognition by, or modulation of, human cells expressing p-gp-mediated MDR.
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PMID:Accumulation of simple organic cations correlates with differential cytotoxicity in multidrug-resistant and -sensitive human and rodent cells. 920 5

Our previous study showed that nicardipine and its structural analog, methyl 2-(N-benzyl-N-methylamino)ethyl-2,6-dimethyl-4-(2-isopropyl-pyrazolo[1,5 -a]pyridine-3-yl)-1,4-dihydro-pyridine-3,5-dicarboxylate (AHC-52), which is devoid of calcium channel blocking activity, were equally effective in inhibiting natural killer (NK) cell activity, perhaps through inhibition of P-glycoprotein. In this study, we confirmed this finding using a human NK-like cell line, YTN, which is highly cytotoxic to JY cells. The YTN cell-mediated cytotoxicity toward JY cells was inhibited by nicardipine and AHC-52 in a concentration-dependent manner, the concentrations required for 50% inhibition being 14 and 7 microM, respectively. We then examined by flow cytometry whether these reagents modulate the intracellular pH (pHi), since P-glycoprotein reportedly plays a role in pHi homeostasis, perhaps by altering chloride translocation. Both reagents reduced pHi at concentrations similar to those required for inhibition of the cytotoxicity. In addition, 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS), an inhibitor of anion exchangers, also inhibited NK cell activity, with an IC50 value of 160 microM, and reduced pHi at a similar concentration, although it is not a P-glycoprotein blocker. Thus, the inhibitory activities of nicardipine, AHC-52, and DIDS toward NK cell activity paralleled their lowering activities of pHi, suggesting the possibility that disregulation of pHi is related to inhibition of NK cell activity.
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PMID:Reduction of intracellular pH by inhibitors of natural killer cell activity, nicardipine, methyl 2-(N-benzyl-N-methylamino)ethyl-2,6-dimethyl-4-(2-isopropyl-pyrazolo[1, 5-a]pyridine-3-yl)-1,4-dihydro-pyridine-3,5-dicarboxylate (AHC-52), and 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS). 929 60

Research on multidrug resistance (MDR) has spread widely, with the emphasis on the development of therapeutic approaches. This line of research began in the early 1970s. In 1981 and 1982, calcium channel blockers such as verapamil and calmodulin inhibitors were found to enhance the intracellular levels of vincristine (VCR) and adriamycin (ADM) in resistant tumor cells by inhibiting their outward transport and to circumvent MDR in animal experiments. Since these results were noted for verapamil, various other compounds have been investigated to overcome drug resistance. Among these compounds, two compounds were evaluated in our laboratory. The non-immunosuppressive cyclosporin derivative SDZ PSC833 (PSC) has been shown to reverse MDR completely in vitro and in vivo. The second compound is MS-209, a novel quinoline derivative. MS209 completely reversed the resistance against VCR and ADM in vitro. MS209 enhanced the chemotherapeutic effects of VCR and ADM in P388/VCR- and P388/ADM-bearing mice. MS-209 has now started clinical trials in Japan. In addition to these chemical agents, monoclonal antibodies (moAb) against P-glycoprotein such as MRK16 could be useful tools for selective killing of MDR tumor cells. Furthermore another moAb MRK17 can be used against human MDR cells transfected with macrophage-colony stimulating factor (M-CSF) gene. M-CSF can act as an enhancer of antibody dependent cellular cytotoxicity (ADCC) in therapy of human MDR cancer with the anti-P-glycoprotein antibody.
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PMID:[Mechanism of multidrug resistant tumors and chemotherapeutic approaches against the resistant tumors]. 930 24

Multiple drug resistance (MDR) mechanisms are known to limit the effectiveness of some cancer chemotherapies, probably through enhancing P-glycoprotein-mediated drug efflux from mammalian cells. Similar mechanisms appear to act in other organisms, including bacteria, and may affect not only the toxicity but also the mutagenicity of certain chemicals. At least in some experimental situations, MDR can be overcome through concomitant treatment of the cells with various types of inhibitors. Two MDR inhibitors, verapamil, a calcium channel blocker, and trifluoperazine, a calmodulin inhibitor, were assayed for their ability to modulate the potency of nine mutagens with varying mechanisms of action in various Salmonella typhimurium his- strains. Neither verapamil nor trifluoperazine affected the direct mutagenicity of sodium dichromate and 2-methoxy-6-chloro-9[3-(2-chloroethyl)amino-propyl-amino] dihydrochloride (ICR 191) or the S9-mediated mutagenicity of benzo[a]pyrene and 2-amino-3,4-dimethyl-amidazo[4,5-f]quinoline (MeIQ). Both modulators enhanced the direct mutagenicity of doxorubicin. Moreover, trifluoperazine sharply increased the S9-mediated mutagenicity of cyclophosphamide and 2-aminofluorene, while it consistently decreased the mutagenicity of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). The contrasting effect towards the aromatic amine 2-aminofluorene and the heterocyclic amine Trp-P-2, representative of important chemical families responsible for the bacterial mutagenicity of cigarette smoke, may explain the observed lack of influence of trifluoperazine on the mutagenicity of a cigarette smoke condensate. These observations extend the known range of chemical types whose mutagenicity can be modulated by inhibitors of MDR and suggest that there may be value in adding MDR inhibitors, especially trifluoperazine, to optimize the detection of mutagenicity by certain types of chemicals in the Salmonella/mammalian microsome mutagenicity test.
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PMID:Modulation of the potency of promutagens and direct acting mutagens in bacteria by inhibitors of the multidrug resistance mechanism. 941 96

P-glycoprotein (Pgp), a membrane drug efflux pump, is thought to be responsible for the observed drug resistance in osteosarcoma. We have recently developed Pgp-positive, multidrug resistant (MDR) murine osteosarcoma cell lines, which may be suitable models for the study of drug resistance in osteosarcoma. In this study, we investigated the effect of a newly synthesized quinoline compound, MS-209, on the reversal of doxorubicin (DOX) resistance in these cell lines. Three different types of resistance modifying agents (RMAs) as well as MS-209 were studied. These included the calcium channel blocker verapamil, and the immunosuppressive agents cyclosporin A and FK506. The reversal effects of the RMAs on DOX resistance were assessed by the MTT assay. In the absence of RMAs, the MDR osteosarcoma cells were 20-fold more resistant to DOX than the parental cells. When MS-209 was added at a final concentration of 0.1 to 3 microM to the MDR cells, 3-to 74-fold sensitization was observed. A complete reversal (37-fold sensitization) of the resistance was obtained at 1 microM MS-209. This concentration of MS-209 was 3-, 8- and 28-fold more effective than the same concentration of FK506, verapamil and cyclosporin A, respectively. These results indicate that MS-209 may be a more effective RMA, and that DOX resistance in osteosarcoma cells could be reversed by comparatively low doses of MS-209.
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PMID:Avoidance of doxorubicin resistance in osteosarcoma cells using a new quinoline derivative, MS-209. 961 13


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