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)

A newly synthesized taxoid originally from the Japanese yew Taxus cuspidata, 5-O-benzoylated taxinine K (BTK) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein (MRP)-mediated multidrug resistance. BTK reversed the resistance to paclitaxel, doxorubicin (ADM), and vincristine (VCR) of KB-8-5 and KB-C2 cells that overexpress P-gp by directly interacting with P-gp. BTK also moderately reversed the resistance to ADM of KB/MRP cells that overexpress MRP. However, BTK neither inhibited the transporting activity of MRP nor reduced intracellular glutathione levels in KB/MRP cells. BTK shifted the distribution of ADM in KB/MRP cells from punctate cytoplasmic compartments to the nucleoplasm and cytoplasm by inhibiting acidification of cytoplasmic organelles. These two functions of BTK make it able to reverse both P-gp- and MRP-mediated MDR. BTK in combination with ADM should be useful for treating patients with tumors that overexpress both P-gp and MRP.
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PMID:Reversal of P-glycoprotein and multidrug-resistance protein-mediated drug resistance in KB cells by 5-O-benzoylated taxinine K. 1109 97

The transport mechanism of the non-sedative H1-antagonist ebastine and its first-pass carboxylic acid metabolite carebastine at the blood-brain barrier (BBB) was studied. In rats, the brain uptake index (BUI) value of [14 C]carebastine was significantly lower than that of [14 C]ebastine. The BUI value of [14 C]carebastine was greatly increased by the addition of non-labeled carebastine. The steady-state uptake of [14 C]carebastine by P-glycoprotein-overexpressing K562/ADM cells was significantly lower than that by their parental drug-sensitive cell line K562. The decreased steady-state uptake of [14 C]carebastine by K562/ADM cells was reversed by verapamil. Steady-state uptake of [14 C]carebastine by primary cultured bovine brain capillary endothelial cells (bovine BCECs) was increased in the presence of metabolic inhibitors and verapamil. Non-labeled carebastine increased the steady-state uptake of a P-glycoprotein substrate, [3 H]vincristine, by bovine BCECs. The initial uptake of [3 H]mepyramine by bovine BCECs and RBEC1 (an immortalized cell line from rat brain capillary endothelial cells) was strongly inhibited by ebastine, while zwitterionic carebastine was slightly inhibitory. The values of brain-to-plasma unbound concentration ratio (Kp,f) in mdr1a(-/-) mice were increased 5.3-fold and 4.2-fold for [14 C ebastine and for [14 C]carebastine, respectively, compared with those in mdr1a(+/+) mice. Non-radiolabeled carebastine increased the Kp,f values of [14 C]carebastine in both types of mice. In conclusion, carebastine was shown to be a substrate for P-glycoprotein-mediated efflux from the brain at the BBB. A second efflux system may also be involved. The relatively low affinity of the uptake transport system for carebastine also limits the brain distribution of ebastine/carebastine.
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PMID:Blood-brain barrier transport of H1-antagonist ebastine and its metabolite carebastine. 1132 64

We investigated the effects of natural flavones, quercetin and morin, and their pentamethyl, pentaethyl, pentapropyl, pentabutyl and pentaallyl ethers, on the function of P-glycoprotein (P-gp) assessed by an increase in the uptake of [3H]vincristine by human myelogenous leukemia (K562) cells and adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. Pentamethyl, pentaethyl, pentapropyl and pentaallyl ethers of morin and quercetin (20 microM) all increased the uptake of [3H]vincristine by K562/ADM cells, while quercetin, morin and their pentabutyl ethers had no effect. Pentamethylquercetin, pentaallylquercetin and pentaethylmorin remarkably increased the uptake of [3H]vincristine by K562/ADM cells by 10.6, 10.8 and 14.4-fold, respectively. These inhibitory potencies for P-gp were more potent than typical P-gp inhibitors, cyclosporine A and verapamil. Taking into consideration that these flavonoid derivatives possess antitumor promoter activity, they may become candidates of effective multidrug resistance-reversing agents in cancer chemotherapy.
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PMID:Inhibition of P-glycoprotein by flavonoid derivatives in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. 1180 35

The existence of multidrug-resistant (MDR) cells in cancer is a major obstacle to effective cancer chemotherapy. Expression of P-glycoprotein (P-gp) in cancer cells causes resistance against paclitaxel and docetaxel, as well as against vincristine and doxorubicin (ADM). MS-209 is a novel MDR-reversal agent currently under clinical evaluation, which is shown to be active against ADM and vincristine resistance in MDR cancer cells in vitro and in vivo. In this paper, we report the combined effect of MS-209 with docetaxel in various MDR cancer cell lines that express P-gp. MS-209 at 3 microM effectively overcame docetaxel resistance in MDR cancer cells, and this concentration was achieved in blood plasma for > 7 h without serious toxicity. To study the effect of MS-209 in a clinically relevant model, we compared the antitumor efficacy of docetaxel alone with that of docetaxel combined with MS-209 at equitoxic doses in established solid tumor xenograft models. Treatment with docetaxel alone at the maximal tolerated dose (MTD) showed an apparent antitumor activity to an intrinsically resistant HCT-15 tumor xenograft, and MS-209 additionally potentiated the antitumor activity of docetaxel. Against a MCF-7/ADM tumor xenograft expressing larger amounts of P-gp, docetaxel alone at the MTD showed no antitumor activity, whereas the MTD of docetaxel combined with MS-209 greatly reduced MCF-7/ADM tumor growth. These results indicate that MS-209 could be a clinically useful drug to modulate MDR in docetaxel therapy.
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PMID:MS-209, a quinoline-type reversal agent, potentiates antitumor efficacy of docetaxel in multidrug-resistant solid tumor xenograft models. 1183 80

STI571, an abl tyrosine kinase inhibitor, is less effective in chronic myelogenous leukemia (CML) patients in the accelerated phase and in blastic crisis. We addressed whether STI571 is effective for the CML blastic crisis cell line K562 and the P-glycoprotein (P-gp) positive, multidrug resistance cell line K562/ADM. The present results demonstrate that P-gp positive K562/ADM cells were more resistant than K562 cells to the anti-proliferative and apoptotic effect of STI571, but the co-addition of a P-gp modulator augmented the sensitivity of K562/ADM cells to STI571. For patients in CML blastic crisis, simultaneous use of a P-gp modulator may increase the efficacy of STI571.
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PMID:Anti-proliferative effect of the abl tyrosine kinase inhibitor STI571 on the P-glycoprotein positive K562/ADM cell line. 1296 24

P-glycoprotein is an efflux pump for a broad spectrum of hydrophobic agents. We found that bioactive peptides including somatostatin and substance P inhibit ATP-dependent vincristine binding to P-glycoprotein-overexpressing K562/ADM membrane vesicles. Some of these bioactive peptides including somatostatin stimulate basal ATPase activity of P-glycoprotein; in contrast, other peptides including substance P inhibit it. The K562/ADM membrane vesicles showed an ATP-dependent, osmotically sensitive uptake of somatostatin and substance P, which was inhibited by valspodar, an inhibitor of P-glycoprotein. These findings suggested that certain bioactive peptides such as somatostatin and substance P directly interact with human P-glycoprotein as endogenous substrates for P-glycoprotein-mediated transport.
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PMID:Transport of somatostatin and substance P by human P-glycoprotein. 1535 39

A major impediment to cancer treatment is the development of resistance by the tumor. P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1) are involved in multidrug resistance. In addition to the extrusion of chemotherapeutic agents through these transporters, it has been reported that there are differences in the intracellular distribution of chemotherapeutic agents between drug resistant cells and sensitive cells. Cepharanthine is a plant alkaloid that effectively reverses resistance to anticancer agents. It has been previously shown that cepharanthine is an effective agent for the reversal of resistance in P-gp-overexpressing cells. Cepharanthine has also been reported to have numerous pharmacological effects besides the inhibition of P-gp. It has also been found that cepharanthine enhanced sensitivity to doxorubicin (ADM) and vincristine (VCR), and enhanced apoptosis induced by ADM and VCR of P-gp negative K562 cells. Cepharanthine changed the distribution of ADM from cytoplasmic vesicles to nucleoplasm in K562 cells by inhibiting the acidification of cytoplasmic organelles. Cepharanthine in combination with ADM should be useful for treating patients with tumors.
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PMID:Cepharanthine potently enhances the sensitivity of anticancer agents in K562 cells. 1595 61

Extensive researches have revealed that arsenical can exert anti-tumor efficacy against several kinds of cancers including leukemia. Though, little is known about the effects of arsenical on leukemia resistant to chemotherapy, emerging as a serious clinical problem. In this study, we tested arsenic trioxide (As(2)O(3))-induced apoptosis in K562/ADM multidrug-resistant leukemic cells and investigated its possible mechanisms. Using microscopy, flow cytometry (FCM) and DNA electrophoresis, we found that As(2)O(3) could induce the cells to undergo G2/M phase arrest and apoptosis. Further, it was shown that the levels of FAS and P53 proteins increased and P-glycoprotein (P-gp) decreased upon drug action by employing FCM. Reverse transcription polymerase chain reaction (RT-PCR) detected increased mRNA product of FAS and caspase-3 genes and reduced MDR1 mRNA. CASPASE-3 activity was also enhanced after As(2)O(3) treatment. However, the expression of BCL-2 protein was not affected by the drug. Taken together, As(2)O(3) is able to reverse the apoptosis resistance in drug-resistant K562/ADM cells by modulating expression or activity of key factors associated with apoptosis induction.
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PMID:Arsenic trioxide overcomes apoptosis inhibition in K562/ADM cells by regulating vital components in apoptotic pathway. 1597 94

A strategy to detect P-glycoprotein (P-gp) on cell membrane and quantify the cell number using electrochemical immunoassay was developed by effective surface immunoreactions and immobilization of cells on a highly hydrophilic interface, which was constructed by adsorption of colloidal gold nanoparticles on a methoxysilyl-terminated (Mos) butyrylchitosan modified glassy carbon electrode (Au-CS/GCE). Atomic force microscopy studies proved that the nanoparticles adsorbed on Mos-butyrylchitosan were efficient in preventing the cell leakage and retaining the activity of immobilized living K562/ADM leukemic cells. The incubation with P-gp monoclonal antibody and then the secondary alkaline phosphatase (AP) conjugated antibody introduced AP onto the K562/ADM cell immobilized on Au-CS/GCE. The bound AP led to an amperometric response of 1-naphthyl phosphate. Under optimal conditions the response was proportional to the logarithm of cell concentration in the range from 5.0 x 10(4) to 1.0 x 10(7) cells mL(-)(1) with a detection limit of 1.0 x 10(4) cells mL(-)(1). The results were comparable to flow cytometric analysis of P-gp expression. This proposed method was practical, convenient, and significant in the clinic and cytobiology.
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PMID:Electrochemical immunoassay of membrane P-glycoprotein by immobilization of cells on gold nanoparticles modified on a methoxysilyl-terminated butyrylchitosan matrix. 1611 90

Thymosin alpha1 (Talpha1), a 28-amino acid peptide, is a well-known immune system enhancer for the treatment of various diseases. In the present investigation, the effects of Talpha1 on the proliferation and apoptosis of human leukemia cell lines (HL-60, K562 and K562/ADM) were studied. The proliferation was significantly depressed after 96 h of treatment with Talpha1, and obvious signs of apoptosis, i.e., cell morphology, nuclei condensation and Annexin V binding, were observed thereafter. Moreover, the up-regulation of Fas/Apol (CD95) and decrease in bcl-2 anti-apoptotic gene expression were observed in apoptotic cells. The expression and the function of P-glycoprotein (P-gp) can be slightly inhibited by Talpha1. It is noteworthy that K562 and K562/ADM were more sensitive than HL-60 cells when subjected to Talpha1. Furthermore, HepG-2, the human hepatoma cell line, displayed significant less sensitivity to Talpha1 than all the human leukemia cell lines. D-Tubocurarine (TUB), a nicotinic acetylcholine receptors (nAChRs) antagonist, significantly antagonized the inhibition effects induced by Talpha1, whereas atropine, a muscarinic acetylcholine receptor antagonist, did not exhibit such effects. All the results indicate that Talpha1 was able to significantly suppress proliferation and induce apoptosis in human leukemia cell lines.
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PMID:Thymosin alpha1 suppresses proliferation and induces apoptosis in human leukemia cell lines. 1664 63


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