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)

The aim of the present study was to investigate the anticancer properties of a set of furanoacridone alkaloids, arborinine and evoxanthine, including the inhibitory effect of P-glycoprotein (Pgp) and the apoptosis-inducing capacity. The tested alkaloids were evaluated for multidrug resistance (MDR)-reversing activity on human Pgp-transfected L5178 mouse lymphoma cells, using the rhodamine-123 (Rh-123) assay. The antiproliferative effects of natural compounds and their interactions with doxorubicin were determined in MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. Apoptosis-inducing activity was additionally measured by means of dual annexin V and propidium iodide staining. RT-PCR was used to test the expression of Pgp mRNA after acridone treatment. All of the acridones investigated increased the accumulation of Rh-123. Gravacridonetriol and gravacridonediol monomethyl ether increased the antiproliferative effect of doxorubicin on resistant L5178 cells. Treatment with these agents resulted in a decrease in Pgp mRNA levels. Naturally occurring acridone alkaloids exhibit a beneficial combination of anticancer effects and, accordingly, the acridone skeleton can be considered useful in the design of novel antiproliferative agents.
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PMID:Antitumour properties of acridone alkaloids on a murine lymphoma cell line. 1903 4

The aim of the present study was to investigate the anticancer properties of five alkaloids isolated from Amaryllidaceae, including the inhibitory effect on P-glycoprotein (P-gp) and the apoptosis-inducing capacity. The tested alkaloids were evaluated for their multidrug resistance (MDR)-reversing activity on human MDR1-gene-transfected L5178 mouse lymphoma cells, using the rhodamine-123 (Rh-123) assay. Trisphaeridine and pretazettine increased the intracellular Rh-123 concentration 30- and 50-fold, respectively, as compared to the non-treated cells, and 2-O-acetyllycorine and trisphaeridine were demonstrated by means of the checkerboard method to enhance the antiproliferative activity of doxorubicin on L5178 MDR mouse lymphoma cells. The MTT assay revealed that pretazettine, trisphaeridine and 2-O-acetyllycorine displayed excellent antiproliferative effects on both the human and the mouse cell lines. The apoptosis-inducing activities of selected agents (2-O-acetyllycorine and trisphaeridine) were measured via acridine orange and ethidium bromide dual staining and flow cytometry of the subG1 population.
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PMID:Antitumor activity of alkaloids derived from Amaryllidaceae species. 1936 23

Glucocorticoids are often used in veterinary cancer patients because of their anti-inflammatory actions, appetite-stimulating effects, ability to decrease nausea and vomiting associated with some chemotherapy agents, and, in some instances, for their cytotoxic actions on susceptible tumour cells. Veterinary oncologists may not consider the possibility that the use of glucocorticoids may adversely affect response to chemotherapy. There is evidence that glucocorticoids can up-regulate the expression of multidrug resistance genes in some tissues. Whether or not glucocorticoid-induced expression of multidrug resistance proteins occurs in tumour cells is not presently known. The purpose of this study was to determine if dexamethasone induces P-glycoprotein (P-gp) or multidrug resistance-related protein 1 (MRP1) in tumour cell lines. A canine osteosarcoma cell line (OS2.4) and a human myeloid leukaemia cell line 60 (HL60) were treated in culture with dexamethasone. The presence of a glucocorticoid receptor was confirmed in both cell lines by reverse-transcriptase polymerase chain reaction. Western blots for P-gp and MRP1 expression were performed on vehicle-treated and dexamethasone-treated cells. Sensitivity towards several chemotherapeutic drugs (cisplatin (cis-diamminedichloroplatinum), doxorubicin, methotrexate and vincristine) was determined by 3-(4,5-dimthylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. While dexamethasone treatment of OS2.4 cells increased the resistance to cisplatin and methotrexate, an increase in P-gp or MRP1 expression was not observed. Dexamethasone-treated HL60 cells did not develop chemoresistance and did not show increased expression of P-gp or MRP1.
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PMID:Dexamethasone treatment of a canine, but not human, tumour cell line increases chemoresistance independent of P-glycoprotein and multidrug resistance-related protein expression. 1937 18

Multidrug resistance (MDR) has been a major problem in cancer chemotherapy. The development of P-glycoprotein inhibitors could be effective to reverse multidrug resistance. The aim of this study was to observe the effects of guggulsterone, the active component of gugulipid, on multidrug resistance in doxorubicin-resistant K562 cells (K562/DOX) and the parental K562 cells. Its cytotoxicity and reversal effects on multidrug resistance were assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Apoptosis percentage of cells was obtained from Annexin V/fluorescein isothiocyanate (FITC) and propridium iodide (PI) double staining. The effects of guggulsterone on P-glycoprotein activity were evaluated by measuring rhodamine 123 (Rh123)-associated mean fluorescence intensity and P-glycoprotein expression on the basis of the flow cytometric technology, respectively. The results showed that guggulsterone up to 100 microM had little cytotoxicity against K562/DOX cells. When combined with doxorubicin, it significantly promoted the sensitivity of K562/DOX cells toward doxorubicin through increasing intracellular accumulation of doxorubicin in a dose-dependent manner. Further study demonstrated that the inhibitory effect of guggulsterone on P-glycoprotein activity was the major cause of increased stagnation of doxorubicin inside K562/DOX cells, indicating that guggulsterone may effectively reverse multidrug resistance in K562/DOX cells via inhibiting expression and drug-transport function of P-glycoprotein.
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PMID:Reversal of P-glycoprotein-mediated multidrug resistance by guggulsterone in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. 1994 69

Cationic paclitaxel nanoparticles were developed and the possible delivery mechanism was explored by cellular uptake studies. In vitro cytotoxicity of paclitaxel-loaded nanoparticles was evaluated with NIH-3T3 cells and multidrug resistant MDR-3T3 cells (with active P-glycoprotein). The IC(50)s of paclitaxel nanoparticles, liposomal paclitaxel, and Taxol((R)) on NIH-3T3 cells were 0.7 microg/mL, 3.0 microg/mL, and 3.6 microg/mL, respectively, and on MDR-3T3 cells changed to 1.4 microg/mL, 4.4 microg/mL, and 7.3 microg/mL respectively. After addition of verapamil (nonspecific P-glycoprotein inhibition), the IC(50)s on MDR-3T3 cells changed to 0.3 microg/mL, 0.7 microg/mL, and 1.5 microg/mL, respectively. The cellular uptake study of NBD-DOPE labeled nanoparticles by MDR-3T3 cells showed more cellular associated fluorescence than neutral liposomes (EPC/cholesterol). The cellular uptake was not affected by verapamil. Fluorescent nanoparticle-encapsulated 10-nonyl bromide acridine orange also demonstrated an enhanced uptake compared to neutral liposomes. The cellular uptake was increased after verapamil's addition. The cellular uptake of formulations with increased positive charges and the competition of free cationic lipid GL89 demonstrated that the positive charge of the particles enhanced the cellular uptake. In conclusion, although the cationic paclitaxel nanoparticle is susceptible to P-glycoprotein efflux, it is still a promising delivery system for paclitaxel, because of enhanced uptake, which resulted in significantly increased cytotoxicity.
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PMID:In vitro cytotoxic activity of cationic paclitaxel nanoparticles on MDR-3T3 cells. 2005 1

Multidrug resistance (MDR) is one of important issues to cause the chemotherapy failure against cancers including gynecological malignancies. Despite some MDR reversal evidences of natural compounds including quinidine and cinchonine, there are no reports on MDR reversal activity of hydrocinchonine with its analogues quinidine and cinchonine especially in uterine sarcoma cells. Thus, in the current study, we comparatively investigated the potent efficacy of hydrocinchonine and its analogues quinidine and cinchonine as MDR-reversal agents for combined therapy with antitumor agent paclitaxel (TAX). Hydrocinchonine, cinchonine, and quinidine significantly increased the cytotoxicity of TAX in P-glycoprotein (gp)-positive MES-SA/DX5, but not in the P-gp-negative MES-SA cells at nontoxic concentrations by 3-(4,5-dimethylthiazol-2-yl)-2,5--diphenyltetrazolium bromide (MTT) assay. Rhodamine assay also revealed that hydrocinchonine, cinchonine, and quinidine effectively enhanced the accumulation of a P-gp substrate, rhodamine in TAX-treated MES-SA/DX5 cells compared with TAX-treated control. In addition, hydrocinchonine, cinchonine, and quinidine effectively cleaved poly (ADP-ribose) polymerase (PARP), activated caspase-3, and downregulated P-gp expression as well as increased sub-G1 apoptotic portion in TAX-treated MES-SA/DX5 cells. Taken together, hydrocinchonine exerted MDR reversal activity and synergistic apoptotic effect with TAX in MES-SA/DX5 cells almost comparable with quinidine and cinchonine as a potent MDR-reversal and combined therapy agent with TAX.
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PMID:Hydrocinchonine, cinchonine, and quinidine potentiate paclitaxel-induced cytotoxicity and apoptosis via multidrug resistance reversal in MES-SA/DX5 uterine sarcoma cells. 2019 46

In photodynamic therapy (PDT) a tumor-selective photosensitizer is administered and then activated by exposure to a light source of appropriate wavelength. Multidrug resistance (MDR) is largely caused by the drug efflux from the tumor cell by means of P-glycoprotein, resulting in reduced efficacy of the anticancer therapy. This study deals with photodynamic therapy with Photofrin (Ph) on colon cancer cell lines (doxorubicin-sensitive and -resistant). The cells were treated with 15 and 30 microg/mL Ph and then irradiated by a light dose of 3 or 6 J/cm(2) (632.8 nm). After irradiation the cells were incubated for 0, 3 or 18 h. Crucial factors of oxidative stress (thiobarbituric acid reactive substances [TBARS], protein damage, thiazolyl blue tetrazolium bromide [MTT] assay), changes in cytosolic superoxide dismutase (SOD1) activity after photodynamic reaction (PDR), and the intracellular accumulation of photosensitizers in the cells were examined. Moreover, the expressions of glutathione S-transferase (GST)-pi, a marker protein for photochemical toxicity, and secretory phospholipase A(2), a prognostic and diagnostic marker for colon cancers, were determined. After PDR, increases in SOD1 activity and the level of TBARS were observed in both cell lines. The level of protein-associated -SH groups decreased after PDR. Both cell lines demonstrated stronger GST-pi and PLA(2) expression after PDR, especially after 18 h of incubation. The increasing level of reactive oxygen species following the oxidation of sulfhydryl cell groups and lipid peroxidation influence the activity of many transporters and enzymes. The changes in SOD1 activity show that photodynamic action generates oxidative stress in treated cells. Our study presents that PDR caused oxidative alterations in both examined colon adenocarcinoma cell lines. However, the MDR cells reacted more slowly and all oxidative changes occurred in the delay.
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PMID:Oxidative alterations induced in vitro by the photodynamic reaction in doxorubicin-sensitive (LoVo) and -resistant (LoVoDX) colon adenocarcinoma cells. 2040 24

Multidrug resistance (MDR) is a serious obstacle to cancer chemotherapy. Overexpression of P-glycoprotein (P-gp), the MDR1 gene product, confers MDR to tumor cells. This study explored the possibility of reducing drug resistance by targeting the mdr1 gene using short hairpin RNA (shRNA). Two different shRNAs were designed and constructed in a pSilencer 2.1-U6 neo plasmid. The shRNA recombinant plasmids were transfected into HT9 leukemia cells. Real-time polymerase chain reaction and Western blotting were used to characterize the inhibited expression of MDR1 mRNA and P-gp, and the drug sensitivity of the transfected cells was assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The results indicated that the inhibition of P-gp expression by small interfering RNA selectively restored sensitivity to the drugs transported by P-gp. Evaluation of chemosensitivity showed 52.58% reversal by p2.1-shRNA1 and 73.07% reversal by p2.1-shRNA2 in drug resistance for harringtonine, and 84.87% reversal by p2.1-shRNA1 and 94.23% reversal by p2.1-shRNA2 in drug resistance for curcumin in the transfected cells. The results demonstrated the efficacy and selectivity of shRNA in reversing MDR in drug-resistant HT9 cells in vitro.
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PMID:Reversal of MDR1 gene-dependent multidrug resistance in HL60/HT9 cells using short hairpin RNA expression vectors. 2042 30

This study investigates the electromagnetic field (EMF)-regulated transport of cationic solid lipid nanoparticles (CSLNs) across human brain-microvascular endothelial cells (HBMECs). The positive charge of CSLNs was from dioctadecyldimethyl ammonium bromide and stearylamine, and radiofrequency EMF was applied to HBMECs for promoting uptake of CSLNs. Immunochemical staining revealed that the expression of clathrin on the membrane of HBMECs enhanced during vesicular endocytosis of CSLNs. However, CSLNs and EMF slightly affected the expression of P-glycoprotein on the membrane of HBMECs. An exposure to EMF yielded negligible increase in the permeability of free saquinavir (SQV) across the HBMEC monolayer. Nevertheless, the permeability of SQV across the HBMEC monolayer increased about 17-fold when SQV was entrapped in CSLNs. Moreover, the permeability of SQV across the HBMEC monolayer increased about 22-fold by applying the CSLN encapsulation and EMF exposure. CSLNs and EMF could produce synergistic effect on improving the brain-targeting delivery.
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PMID:Effect of electromagnetic field on endocytosis of cationic solid lipid nanoparticles by human brain-microvascular endothelial cells. 2052 98

Urinary bladder cancer is one of the most common cancers worldwide. Human transitional cell carcinoma (TCC) cells are epithelial-like adherent cells originally established from a primary bladder carcinoma. Studies have shown that TCC cells are resistant to some chemotherapeutic agents such as vincristine (VCR). In the present study, the effect of feselol, a sesquiterpene coumarin isolated from the fruits of Ferula badrakema, was investigated on VCR effectiveness. Our results demonstrated that feselol itself did not have any cytotoxic effect on TCC cells. In order to check its combinatorial effects, TCC cells were exposed to various combined concentrations of feselol and VCR. Then, morphological changes were monitored and cytotoxicity was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay for three consequent days. Results showed that the combination of 40 microg/ml VCR with 16 microg/ml feselol increased the cytotoxicity of VCR by 28.32% after 48 h. This effect might be due to inhibition of P-glycoprotein in TCC cells by feselol.
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PMID:The enhancement of vincristine cytotoxicity by combination with feselol. 2062 35


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