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)

Two vincristine-resistant Chinese hamster ovary cell lines have been shown previously to be hypersensitive to the calcium channel blocker, verapamil. They are now shown to be hypersensitive to the membrane-active agent quinidine sulfate and to the calcium channel blockers diltiazem and nicardipine. Hypersensitivity to quinidine sulfate implies that calcium channels are not the primary target for these drug effects on these cell lines and is consistent with our previous observation that their calcium accumulation is normal in the presence and absence of verapamil. The two cell lines have elevated levels of membrane P-glycoprotein and of two cytosolic proteins, Mr 27,000 and pI 6.0 and 6.4. Revertants have normal levels of these cytosolic proteins, suggesting that these proteins may play a role in conferring resistance. [3H]Verapamil accumulation by the two cell lines is lower than in controls. One of the cell lines has been hybridized to normal cells and the vincristine resistance and verapamil sensitivity of three hybrid clones has been determined. Vincristine resistance is semidominant but verapamil hypersensitivity is completely recessive.
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PMID:Properties of verapamil-hypersensitive multidrug-resistant Chinese hamster ovary cells. 289 55

Verapamil, a phenylalkylamine calcium channel blocker, has been shown to reverse multidrug resistance in tumor cells, possibly by increasing drug retention through interaction with an outward drug transporter of the resistant cells. In this study two photoactive radioactive analogs of verapamil, N-(p-azido[3,5-3H]benzoyl)aminomethyl verapamil and N-(p-azido[3-125I]salicyl)aminomethyl verapamil, were synthesized and used to identify the possible biochemical target(s) for verapamil in multidrug-resistant DC-3F/VCRd-5L Chinese hamster lung cells selected for resistance to vincristine. The results show that a specifically labeled 150- to 180-kDa membrane protein in resistant cells was immunoprecipitated with a monoclonal antibody specific for P-glycoprotein. Phenylalkylamine binding specificity was established by competitive blocking of specific photolabeling with the nonradioactive photoactive analogs as well as with verapamil. Photoaffinity labeling was also inhibited by 50 microM concentrations of the calcium channel blockers nimodipine, nifedipine, nicardipine, azidopine, bepridil, and diltiazem and partially by prenylamine. Bay K8644, a calcium channel agonist, also inhibited P-glycoprotein photolabeling. Moreover, P-glycoprotein labeling was inhibited in a dose-dependent manner by vinblastine with half-maximal inhibition at 0.2 microM compared to that by verapamil at 8 microM. Photolabeling was also partially inhibited by two of the drugs to which these cells are cross-resistant, doxorubicin and actinomycin D, at 100 microM, but not by colchicine. These data provide direct evidence that P-glycoprotein has broad drug recognition capacity and that it serves as a molecular target for calcium channel blocker action in reversing multidrug resistance.
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PMID:Photoaffinity labeling of the multidrug-resistance-related P-glycoprotein with photoactive analogs of verapamil. 290 25

MDR1 gene encodes a membrane glycoprotein (P-glycoprotein) that acts as a energy-dependent pump to transport antitumor drugs out of the cells. P-glycoprotein, 1280 amino acids long, consists of two homologous parts of approximately equal length. The protein has binding sites for ATP, antitumor drugs and calcium channel blockers. MDR1 gene is expressed tissue-specific in human normal adrenal, kidney, liver and colon. The normal function and transcriptional regulation of this gene are also discussed.
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PMID:[The multidrug-resistance gene MDR1]. 290 31

A radioactive photoactive dihydropyridine calcium channel blocker, [3H]azidopine, was used to photoaffinity label plasma membranes of multidrug-resistant Chinese hamster lung cells selected for resistance to vincristine (DC-3F/VCRd-5L) or actinomycin D (DC-3F/ADX). Sodium dodecyl sulfate-polyacrylamide gel electrophoretic fluorograms revealed the presence of an intensely radiolabeled 150-180-kDa doublet in the membranes from drug-resistant but not from the drug-sensitive parental (DC-3F) cells. A similar radiolabeled doublet was barely detected in a drug-sensitive partial revertant (DC-3F/ADX-U) cell line. The 150-180-kDa doublet exhibited a specific half-maximal saturable photolabeling at 1.07 X 10(-7) M [3H]azidopine. The dihydropyridine binding specificity was established by competitive blocking of specific photolabeling with nonradioactive azidopine as well as with nonphotoactive calcium channel blockers nimodipine, nitrendipine, and nifedipine. In addition, [3H]azidopine photolabeling was blocked by verapamil and diltiazem but was stimulated by excess prenylamine and bepridil suggesting a cross-specificity for up to four different classes of calcium channel blockers. The 150-180-kDa calcium channel blocker acceptor co-electrophoresed exactly with the 150-180-kDa surface membrane glycoprotein (gp150-180 or P-glycoprotein) Vinca alkaloid acceptor from multidrug-resistant cells and was immunoprecipitated by polyclonal antibody recognizing gp150-180. [3H]Azidopine photolabeling of the 150-180-kDa component in the presence of excess vinblastine was reduced over 90%, confirming the identity or close relationship of the calcium channel blocker acceptor and the gp150-180 Vinca alkaloid acceptor. The [3H]azidopine photolabeling of gp150-180 also was reduced by excess actinomycin D, adriamycin, or colchicine, demonstrating a broad gp150-180 drug recognition capacity. The ability of gp150-180 to recognize multiple natural product cytotoxic drugs as well as calcium channel blockers suggests a direct function for gp150-180 in the multidrug resistance phenomenon and a role in the circumvention of that resistance by calcium channel blockers.
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PMID:Identification of the multidrug resistance-related membrane glycoprotein as an acceptor for calcium channel blockers. 303 8

To analyze the mechanism of drug transport, mechanism of inhibitors, and physiological substrates of human P-glycoprotein, we established a transepithelial transport system by introducing MDR1 cDNA into LLC-PK1, a pig kidney epithelial cell line. P-glycoprotein functions as a steroid transporter as well as a drug transporter as physiological functions. P-glycoprotein also transports MDR modulators such as cyclosporin A, FK506, and calcium channel blockers.
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PMID:Human P-glycoprotein as a multi-drug transporter analyzed by using transepithelial transport system. 753 9

P-glycoprotein modulators are respected to be multidrug resistance reversing agents in cancer chemotherapy. Some calcium channel blockers, calmodulin inhibitors or immunosuppressive agents have been used in clinical studies, although the dose of these drugs required to test in vitro experimental data might cause potent pharmacological effects which are not desirable in patients. By using LLC-GA5-COL150 cells that express P-glycoprotein specifically on the apical membranes, we examined the transport of anticancer drugs mediated by P-glycoprotein. Cepharanthin, a biscoclaurine alkaloid, potently inhibits the transport of vinblastine and daunorubicin, both commonly used anticancer agents. The 50% inhibitory concentration of cepharanthin on daunorubicin transport was 2.06 microM. Combined inhibitory effects on daunorubicin transport were observed when cepharanthin was used together with cyclosporin A, a potent immunosuppressive agent and P-glycoprotein modulator. Cepharanthin itself was transported by P-glycoprotein. Transcellular transport of cepharanthin across LLC-GA5-COL150 cell monolayers was saturable when its concentration was under 5 microM, and the transport was inhibited by P-glycoprotein modulators. These results indicate that cepharanthin can reverse multidrug resistance, and proper combination with other P-glycoprotein modulators could potentiate its inhibitory effect on expelling the anticancer drugs out of the cell via P-glycoprotein.
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PMID:Cepharanthin, a multidrug resistant modifier, is a substrate for P-glycoprotein. 756 98

The basic distinguishing feature of multidrug resistant (MDR) cells is a decrease in steady-state drug levels as compared to drug-sensitive controls. It is well-known that verapamil increases the sensitivity of MDR cells to drugs, thus reverting drug resistance. A limiting factor for its clinical use is the pronounced cardiovascular effects of the calcium channel antagonist which occur at the high plasma concentrations required to block P-glycoprotein transport efficiently. From a clinical point of view, it is important to find verapamil derivatives with low calcium channel blocking activity and high reverting activity. This was the aim of the present study. In this context we have investigated the ability of 20 verapamil analogues with restricted molecular flexibility to increase cellular accumulation of anticancer drugs and overcome resistance, and their inotropic, chronotropic, and slow calcium channel antagonistic activity. In this study an anthracycline derivative 4'-O-tetrahydropyranyl adriamycin, and an erythroleukaemia K562 cell line were used. Three of the 20 derivatives checked were completely devoid of calcium channel blocking activity while exhibiting MDR reverting ability comparable to that of verapamil. These derivatives could be useful for the treatment of MDR in cancer patients and for the design and development of other verapamil derivatives.
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PMID:Reversal of multidrug resistance by verapamil analogues. 764 49

Multidrug resistant cells may become acutely sensitive to the calcium channel blocker verapamil, in spite of the fact that its accumulation by these cells is negligible. We selected verapamil-resistant mutants from multidrug resistant Chinese hamster ovary cells. Levels of P-glycoprotein expression and cross-resistance profiles remained unaltered in the verapamil-resistant multidrug resistant cells. As well, a photoactive verapamil analog specifically bound to P-glycoprotein in these cells. We had previously used a photoactive anthracycline to show that calcium antagonists and several anticancer drugs bind to P-glycoprotein at overlapping or interacting sites. Verapamil and its analogues no longer inhibit the binding of either anticancer drugs or calcium channel blockers to P-glycoprotein. Sequencing of P-glycoprotein revealed that no change had occurred in the coding sequence as a result of the selection procedure.
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PMID:Selection and characterization of verapamil-resistant multidrug resistant cells. 773 17

The ability of malignant cells to develop resistance to chemotherapeutic drugs is a major obstacle to the successful treatment of clinical tumors. The phenomenon multidrug resistance (MDR) in cancer cells results in cross-resistance to a broad range of structurally diverse antineoplastic agents, due to outward efflux of cytotoxic substrates by the mdr1 gene product, P-glycoprotein (P-gp). Numerous pharmacologic agents have been identified which inhibit the efflux pump and modulate MDR. The biochemical, cellular and clinical pharmacology of agents used to circumvent MDR is analyzed in terms of their mechanism of action and potential clinical utility. MDR antagonists, termed chemosensitizers, may be grouped into several classes, and include calcium channel blockers, calmodulin antagonists, anthracycline and Vinca alkaloid analogs, cyclosporines, dipyridamole, and other hydrophobic, cationic compounds. Structural features important for chemosensitizer activity have been identified, and a model for the interaction of these drugs with P-gp is proposed. Other possible cellular targets for the reversal of MDR are also discussed, such as protein kinase C. Strategies for the clinical modulation of MDR and trials combining chemosensitizers with chemotherapeutic drugs in humans are reviewed. Several novel approaches for the modulation of MDR are examined.
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PMID:Pharmacologic circumvention of multidrug resistance. 776 25

Flunarizine, a diphenylpiperazine calcium channel blocker, is known to increase tumor blood flow. It also interferes with calmodulin function, repair of DNA damage and drug resistance associated with P-glycoprotein. Flunarizine was tested for its ability to modulate either cyclophosphamide- or melphalan-induced growth delay for a drug-resistant rhabdomyosarcoma xenograft (TE-671 MR) and the drug-sensitive parent line (TE-671), in which P-glycoprotein is not involved in the mechanism of drug resistance. Tumour blood flow was increased by 30% after a flunarizine dose of 4 mg kg-1, but no modification in growth delay was induced by melphalan (12 mg kg-1). In contrast, a 60 mg kg-1 dose of flunarizine had no effect on tumour blood flow, but the same dose created significant enhancement in melphalan-induced tumour regrowth delay in both tumour lines. The dose-modifying factor for flunarizine as an adjuvant to melphalan was approximately 2 for both tumour lines. Although blood flow measurements were not performed with the combination of flunarizine and melphalan, the results from flunarizine alone suggested that augmentation of melphalan cytotoxicity is not mediated by changes in blood flow. In contrast, flunarizine did not affect drug sensitivity to cyclophosphamide in groups of animals bearing the drug-sensitive parent tumour line. These results suggest that the mechanism of drug sensitivity modification by flunarizine is not related to modification of tumour blood flow, but may be mediated by modification of transport mechanisms that are differentially responsible for cellular uptake and retention of melphalan as compared with cyclophosphamide.
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PMID:Flunarizine enhancement of melphalan activity against drug-sensitive/resistant rhabdomyosarcoma. 777 8


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