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)

We have been studying the resistance mechanisms of various antitumor drugs and screening substances from natural and synthetic products which overcome resistance. In this paper, we described compounds mainly obtained from our screening systems. I. Circumvention of multidrug resistance (MDR). Lactoquinomycin was discovered from the culture broth of a strain of Streptomyces sp. and it showed preferential growth inhibition against multidrug-resistant L5178 Y cells. The mechanism of action of lactoquinomycin was studied. Another novel antibiotic, resorthiomycin, exhibited not only preferential inhibition against MDR tumor cells but also augmentation of cytotoxicity of several antitumor drugs. As synthetic potentiators, dipyridamole, cepharanthine, AHC-52 and analogs of dihydropyridines were described; all of them were thought to interact with a P-glycoprotein and inhibit active efflux of drugs from tumor cells. SDB-ethylenediamine was unique because it overcame MDR and also potentiates a wide range of antitumor drugs including 5-FU and bleomycin. II. E-64 was found to inhibit the activity of a bleomycin-inactivating enzyme. It potentiated the activity of peplomycin in vitro and in vivo. III. Cadeguomycin was discovered from the culture filtrate of a Streptomyces sp. and it potentiated Ara-C by inhibition of the activity of dCMP deaminase, an Ara-C-inactivating enzyme.
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PMID:[Antitumor drugs and potentiators aiming circumvention of drug resistance]. 168 86

Natural killer (NK) cells have been reported recently to be the highest in expressing multidrug resistance (MDR) P-glycoprotein among normal mature lymphoid cells. Using a cultured NK cell-rich population, we have examined the expression and function of P-glycoprotein, in particular its role in NK cell-mediated cytotoxicity, by employing two MDR-reversing agents (nicardipine and AHC-52, a nicardipine analog almost devoid of calcium channel blocking activity) and monoclonal antibody against P-glycoprotein (MRK-16). The expression of P-glycoprotein was detected by flow cytometry and polymerase chain reaction of reverse transcribed mRNA. P-glycoprotein was functional in terms of rhodamine dye excretion and its susceptibility to the MDR-reversing agents. Since the concentration of nicardipine required for 50% inhibition (IC50) of rhodamine dye excretion (2 microM) was close to that of AHC-52 (5 microM), it was suggested that their inhibitory effects were not due to calcium channel blocking activity, and that ACH-52 is a selective inhibitor for P-glycoprotein. The IC50 of nicardipine for NK cell-mediated cytotoxicity (33 microM) was also close to that of AHC-52 (26 microM), indicating that P-glycoprotein is involved in NK cell-mediated cytotoxicity. In support of this, MRK16 inhibited NK cell-mediated cytotoxicity in a concentration-dependent manner. Both binding of target cells to NK cells and post-binding events were affected by AHC-52, suggesting that P-glycoprotein is involved in several steps in NK cell-mediated cytotoxicity.
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PMID:Expression and function of multidrug resistance P-glycoprotein in a cultured natural killer cell-rich population revealed by MRK16 monoclonal antibody and AHC-52. 798 Jun 29

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

Natural killer (NK) cells express the highest amount of P-glycoprotein (Pgp), a product of the multidrug resistance (MDR) 1 gene, among lymphoid cells, and our previous studies demonstrated that Pgp is required for NK cell-mediated cytotoxicity. In this study we examined the role of Pgp in NK cell-mediated cytotoxicity using a human NK-like cell line, i.e., YTN cells and two MDR reversing agents, nicardipine and its structural analog, AHC-93. These two agents inhibited the Pgp function (rhodamine-123 excretion) as well as cell-mediated cytotoxicity, confirming that Pgp is critical for NK cell-mediated cytotoxicity. As revealed by video-rate ultraviolet laser-scanning confocal microscopy, AHC-93 did not inhibit the increase in the intracellular calcium concentration upon binding to target cells, whereas nicardipine did, as reported previously. These two reagents relocated acridine orange dye from lysosomes to the cytoplasm at concentrations similar to those required for the inhibition of cell-mediated cytotoxicity. These results suggest that Pgp is directly or indirectly involved in pH regulation in lysosomes, but not in calcium homeostasis.
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PMID:Role of P-glycoprotein in human natural killer-like cell line-mediated cytotoxicity. 1058 62