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)

Here we firstly investigated the role of miR-138 in multidrug resistance of leukemia cells. miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin. miR-138 could significantly down-regulate the expression of P-glycoprotein, Bcl-2, and the transcription of the multidrug resistance gene 1. Further study of the biological functions of miR-138 might be helpful for developing possible strategies to treat leukemia.
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PMID:miR-138 might reverse multidrug resistance of leukemia cells. 2828 24

Multidrug resistance (MDR) is a major obstacle to cancer chemotherapy. We evaluated the effect of daunorubicin (DNR)-loaded magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) on K562-n/VCR cells in vivo. K562-n and its MDR counterpart K562-n/VCR cell were inoculated into nude mice subcutaneously. The mice were randomly divided into four groups: group A received normal saline, group B received DNR, group C received MNPs-Fe3O4, and group D received DNR-loaded MNPs-Fe3O4. For K562-n/VCR tumor, the weight was markedly lower in group D than that in groups A, B, and C. The transcriptions of Mdr-1 and Bcl-2 gene were significantly lower in group D than those in groups A, B, and C. The expression of Bcl-2 was lower in group D than those in groups A, B, and C, but there was no difference in the expression of P-glycoprotein. The transcriptions and expressions of Bax and caspase-3 in group D were increased significantly when compared with groups A, B, and C. In conclusion, DNR-loaded MNPs-Fe3O4 can overcome MDR in vivo.
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PMID:Daunorubicin-loaded magnetic nanoparticles of Fe3O4 overcome multidrug resistance and induce apoptosis of K562-n/VCR cells in vivo. 1991 66

Overexpression of multidrug resistance proteins P-glycoprotein (P-gp, MDR1) causes resistance of the tumor cells against a variety of chemotherapeutic agents. 3-(1-methyl-1H-indol-3-yl)-1-phenyl-4-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1H-pyrrole-2,5-dione (YQ36) is a novel analogue of bisindolylmaleimide, which has been reported to overcome multidrug resistance. Here, we dedicated to investigate the anticancer activity of YQ36 on KB/VCR cells. The results revealed that YQ36 exhibited great antiproliferative activity on three parental cell lines and MDR1 overexpressed cell lines. Moreover, the hypersensitivity of YQ36 was confirmed on the base of great apoptosis induction and unaltered intracellular drug accumulation in KB/VCR cells. Further results suggested that YQ36 could not be considered as a substrate of P-gp, which contributed to its successfully escaping from the efflux mediated by P-gp. Interestingly, we observed that YQ36 could accumulate in nucleus and induce DNA damage. YQ36 could also induce the activation of caspase-3, imposing effects on the mitochondrial function. Collectively, our data demonstrated that YQ36 exhibited potent activities against MDR cells, inducing DNA damage and triggering subsequent apoptosis via mitochondrial pathway.
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PMID:YQ36: a novel bisindolylmaleimide analogue induces KB/VCR cell death. 2006 25

A new series of 4 beta-anilino-podophyllotoxin analogs have been designed, synthesized and evaluated their bioactivities as novel DNA-topoisomerase II poisons as well as P-glycoprotein (P-gp)-dependent multidrug resistance (MDR) inhibitors. The new compounds show improved potency and efficacy with respect to the parent molecule etoposide (VP-16), one of the semisynthetic derivatives of podophyllotoxin. The treatment of 5k-n in KB/VCR cells caused G(2)/M phase arrest and finally induced apoptosis. Furthermore, molecular docking is applied to testify that 5k-n could not be the substrates of P-gp, which is consistent with the result of MDR1 and P-glycoprotein express tests. The most potent compound 5n is chosen for in vivo studies, the administration of 5n was effective in treatment of cancer with a lower dose than VP-16 in drug-sensitive xenograft model and drug-resistant xenograft model. Compound 5n is a potential drug candidate for anticancer chemotherapy.
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PMID:Novel 4 beta-anilino-podophyllotoxin derivatives: design synthesis and biological evaluation as potent DNA-topoisomerase II poisons and anti-MDR agents. 2009 61

Compound 8H is a phenylcinnamide that induces G2/M-phase cell cycle arrest and cell death in cancer cell lines. Here we show that 8H exerts its cytotoxic activity through disruption of microtubule dynamics in vitro and in cell culture. A series of cinnamide derivatives were synthesized and evaluated, and several new compounds were identified that improve on the activity of the parent compound, with IC(50) values for induction of cell death ranging from 1 to 10 microM. Notably, these compounds retain potency in the HL-60/VCR leukemia cell line, which is resistant to antimitotic cancer drugs vincrisitine and paclitaxel through up-regulation of P-glycoprotein drug efflux pumps. As P-glycoprotein expression is often responsible for drug resistance in cancer and the exclusion of compounds from the central nervous system, 8H and its derivatives merit further examination as potential antimitotic therapeutics, specifically for brain cancers and cancers that are resistant to standard antimitotic agents.
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PMID:Phenylcinnamides as novel antimitotic agents. 2041 88

P-glycoprotein (P-gp) is known to mediate multidrug resistance (MDR) by acting as an efflux pump to actively transport chemotherapeutic agents out of carcinoma cells. Inhibition of P-gp function may represent one of the strategies to reverse MDR. We have previously reported that marchantin C (MC), a macrocyclic bisbibenzyl compound from liverworts, exerts anti-tumor activity as an antimitotic agent. This study was designed to evaluate the possible modulatory effect of MC and its three synthetic derivatives (MC1, MC2 and MC3) on P-gp in VCR-resistant KB/VCR cells. Results of the cytotoxicity assay revealed that MC was the most potent inhibitor of cell proliferation in both KB and KB/VCR cells among these four compounds, while the three MC-derived chemicals had little anti-proliferative activity under the same condition. However, in P-gp-expressing MDR cells, analysis of potency of these compounds in enhancing cytotoxicity of VCR led to the identification of MC2 as a more effective chemical on reversal of resistance. Further study showed that MC2 was able to reduce efflux of rhodamine-123, and in turn, increase the accumulation of rhodamine-123 and adriamycin in KB/VCR cells, indicating that MC2 re-sensitized cells to VCR by inhibition of the P-gp transport activity. In addition, the combination of MC2 and VCR at a concentration that does not inhibit cell growth resulted in an induction of apoptosis in KB/VCR cells. These results suggest that MC2, as a novel and effective inhibitor of P-gp, may find potential application as an adjunctive agent with conventional chemotherapeutic drugs to reverse MDR in P-gp overexpressing cancer cells.
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PMID:Bisbibenzyl derivatives sensitize vincristine-resistant KB/VCR cells to chemotherapeutic agents by retarding P-gp activity. 2072 70

Overexpression of multidrug resistance 1 (MDR1) in cancer remains one of the major causes for the failure of chemotherapy. In the present study, we found that MyoD and PEA3 could activate P-glycoprotein (P-gp) expression in SGC7901 cells. Knockdown of MyoD and PEA3 attenuated MDR1 expression and increased the sensitivity of multidrug resistant cancer cells to cytotoxic drugs that were transported by P-gp in SGC7901/VCR cells. MyoD or PEA3 could bind to the E-box and PEA3 sites on the MDR1 promoter and activate its transcription. The regulation of MDR1 expression by MyoD and PEA3 may provide potential ways to overcome MDR in cancer treatment.
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PMID:Involvement of MyoD and PEA3 in regulation of transcription activity of MDR1 gene. 2098 Mar 37

In order to investigate the effect of rapamycin on the proliferation of human acute myeloid leukemia (AML) cells, the sensitive cells HL-60 and multidrug-resistant HL-60/VCR cells were chosen as research objects. The proliferation of cells was detected by growth curve method. The flow cytometer was used to analyze cell cycle. The expression of P-glycoprotein (Pgp) was determined by Western blot. The results demonstrated that there was a significant difference of cell growth inhibition rate between control group and rapamycin group (p < 0.05). The cell growth inhibition rate was dose- and time- dependent (p < 0.05). Flow cytometry detection showed that the cell percentage of G(1) phase in rapamycin group was higher than that in group without rapamycin, and that of S phase was lower. The cell growth inhibition rate in 50 nmol/L and 100 nmol/L rapamycin plus daunorubicin (DNR) group was more than that in DNR alone group (p < 0.05), especially when DNR was added at 24 hours interval after RAP. The expression of Pgp of HL-60/VCR cells was inhibited by rapamycin. It is concluded that the rapamycin can inhibit the proliferation of sensitive HL-60 and multidrug resistant HL-60/VCR cells. It can also increase sensitivity of HL-60 and HL-60/VCR cells to DNR, which provides new strategy for the therapy of refractory AML.
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PMID:[Effect of rapamycin on proliferation of acute myeloid leukemia cell lines HL-60 and HL-60/VCR]. 2117 52

Cross-drug resistance in multidrug-resistant (MDR) cells, which overexpress P-glycoprotein (P-gp) encoded by the MDR1 gene, is a major impediment to successful chemotherapy for colorectal cancer. In the present study, drug-sensitive HCT8 and multidrug-resistant (vincristine, VCR) HCT8/V colorectal cancer cell lines were used to examine the role of c-Jun NH2-Terminal Kinase- (JNK) signaling pathway in P-gp-mediated MDR associated with Cyclo-oxygenase-2 (COX-2). The results showed that SP600125, a JNK inhibitor, and NS-398, a COX-2 inhibitor, significantly reduced the degree of MDR in HCT8/V cells. This was accompanied by a significant decrease in gene level of MDR1 and protein level of P-gp in HCT8/V cells. Notably, addition of a JNK inhibitor had no significant effect on the expression of COX-2 in both HCT8 and HCT8/V cells. Interestingly, inhibition of COX-2 activity by a chemical inhibitor or its silence by small interfering RNA significantly decreased the level of phosphorylated c-Jun at Ser63/73 in HCT8/V cells. In contrast, upregulation of COX-2 significantly increased the levels of P-gp and p-c-Jun at Ser63/73 in HCT8 cells, but not in HCT8/V cells. Moreover, the intracellular vincristine accumulation in HCT8/V cells significantly increased after inhibiting COX-2 and JNK activity. Taken together, our study has provided the first direct evidence that COX-2 contributes to P-gp-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer cells.
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PMID:COX-2 contributes to P-glycoprotein-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer. 2129 66

The over-expression of P-glycoprotein (P-gp) is associated with the development of multi-drug resistance (MDR) in cancer cells. In this study, we examined whether cationic submicron emulsions (CSEs) can efficiently deliver hydroxycamptothecin (HCPT) into MDR cells (SGC7901/VCR cells) via electrostatic-mediated endocytosis, thus overcoming MDR. We prepared HCPT-CSEs and rhodamine-123-CSEs (RH-123-CSEs), and examined the in vitro cytotoxic activity of HCPT-CSEs and the intracellular accumulation of HCPT and RH-123 in SGC7901/VCR cells. The HCPT-CSEs significantly increased the intracellular accumulation of HCPT (8.2-fold higher than HCPT-injection) and enhanced cytotoxic activity of HCPT (2.7-fold higher than HCPT-injection with verapamil). The fluorescence microscopic and flow cytometric detection on RH-123 supported the intracellular accumulation effect of CSEs. These results indicate CSEs may enhance drug-CSEs internalization followed by releasing their contents into the cytoplasm (near nuclear), thus lowering P-gp-mediated drug efflux. Furthermore, these in vitro results suggest that CSEs are a potentially useful drug delivery system to circumvent P-gp-mediated MDR of tumor cells.
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PMID:Cationic submicron emulsions overcome multidrug resistance in SGC7901/VCR cells. 2143 76


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