Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P(2) receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P(2) not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions.
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PMID:Sphingosine 1-phosphate modulates antigen capture by murine Langerhans cells via the S1P2 receptor subtype. 2314 72

The chemopreventive activity of green tea (GT) is limited by the low bioavailability and extensive methylation of GT polyphenols (GTPs) in vivo. We determined whether a methylation inhibitor quercetin (Q) will enhance the chemoprevention of prostate cancer in vivo. Androgen-sensitive LAPC-4 prostate cancer cells were injected subcutaneously into severe combined immunodeficiency (SCID) mice one week before the intervention. The concentration of GTPs in brewed tea administered as drinking water was 0.07% and Q was supplemented in diet at 0.2% or 0.4%. After 6-weeks of intervention tumor growth was inhibited by 3% (0.2% Q), 15% (0.4% Q), 21% (GT), 28% (GT+0.2% Q) and 45% (GT+0.4% Q) compared to control. The concentration of non-methylated GTPs was significantly increased in tumor tissue with GT+0.4% Q treatment compared to GT alone, and was associated with a decreased protein expression of catechol-O-methyltransferase and multidrug resistance-associated protein (MRP)-1. The combination treatment was also associated with a significant increase in the inhibition of proliferation, androgen receptor and phosphatidylinositol 3-kinase/Akt signaling, and stimulation of apoptosis. The combined effect of GT+0.4% Q on tumor inhibition was further confirmed in another experiment where the intervention started prior to tumor inoculation. These results provide a novel regimen by combining GT and Q to improve chemoprevention in a non-toxic manner and warrant future studies in humans.
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PMID:Enhanced inhibition of prostate cancer xenograft tumor growth by combining quercetin and green tea. 2431 68

Chemotherapy resistance represents a major problem for the treatment of patients with breast cancer and greatly restricts the use of first-line chemotherapeutics paclitaxel. The purpose of this study was to investigate the role of transgelin 2 in human breast cancer paclitaxel resistance cell line (MCF-7/PTX) and the reversal mechanism of salvianolic acid A (SAA), a phenolic active compound extracted from Salvia miltiorrhiza. Western blotting and real-time quantitative polymerase chain reaction (qRT-PCR) indicated that transgelin 2 may mediate paclitaxel resistance by activating the phosphatidylinositol 3-kinase (PI3 K)/Akt signaling pathway to suppress MCF-7/PTX cells apoptosis. The reversal ability of SAA was confirmed by MTT assay and flow cytometry, with a superior 9.1-fold reversal index and enhancement of the apoptotic cytotoxicity induced by paclitaxel. In addition, SAA effectively prevented transgelin 2 and adenosine-triphosphate binding cassette transporter (ABC transporter) including P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1), and breast cancer resistance protein (BCRP) up-regulation and exhibited inhibitory effect on PI3 K/Akt signaling pathway in MCF-7/PTX cells. Taken together, SAA can reverse paclitaxel resistance through suppressing transgelin 2 expression by mechanisms involving attenuation of PI3 K/Akt pathway activation and ABC transporter up-regulation. These results not only provide insight into the potential application of SAA in reversing paclitaxel resistance, thus facilitating the sensitivity of breast cancer chemotherapy, but also highlight a potential role of transgelin 2 in the development of paclitaxel resistance in breast cancer.
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PMID:Salvianolic acid A reverses paclitaxel resistance in human breast cancer MCF-7 cells via targeting the expression of transgelin 2 and attenuating PI3 K/Akt pathway. 2544 83

CUDC-907 is a novel, dual-acting small molecule compound designed to simultaneously inhibit the activity of histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K). Treatment with CUDC-907 led to sustained inhibition of HDAC and PI3K activity, inhibition of RAF-MEK-MAPK signaling pathway, and inhibition of cancer cell growth. CUDC-907 is currently under evaluation in phase I clinical trials in patients with lymphoma or multiple myeloma, and in patients with advanced solid tumors. However, the risk of developing acquired resistance to CUDC-907 can present a significant therapeutic challenge to clinicians in the future and should be investigated. The overexpression of ATP-binding cassette (ABC) drug transporter ABCB1, ABCC1, or ABCG2 is one of the most common mechanisms of developing multidrug resistance (MDR) in cancers and a major obstacle in chemotherapy. In this study, we reveal that ABCG2 reduces the intracellular accumulation of CUDC-907 and confers significant resistance to CUDC-907, which leads to reduced activity of CUDC-907 to inhibit HDAC and PI3K in human cancer cells. Moreover, although CUDC-907 affects the transport function of ABCG2, it was not potent enough to reverse drug resistance mediated by ABCG2 or affect the expression level of ABCG2 in human cancer cells. Taken together, our findings indicate that ABCG2-mediated CUDC-907 resistance can have serious clinical implications and should be further investigated. More importantly, we demonstrate that the activity of CUDC-907 in ABCG2-overexpressing cancer cells can be restored by inhibiting the function of ABCG2, which provides support for the rationale of combining CUDC-907 with modulators of ABCG2 to improve the pharmacokinetics and efficacy of CUDC-907 in future treatment trials.
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PMID:Human ATP-Binding Cassette Transporter ABCG2 Confers Resistance to CUDC-907, a Dual Inhibitor of Histone Deacetylase and Phosphatidylinositol 3-Kinase. 2679 63

Therapeutic effects of anti-cancer drugs for ovarian cancer were limited due to the rapid development of chemotherapy resistance. The aim of this study was to test whether knockdown of Homeobox B4 (HOXB4) enhanced the cytotoxic effect of paclitaxel and cisplatin in ovarian cancer cells. HOXB4 expressions at mRNA and protein levels were upregulated in Taxol-resistant A2780 (A2780/Taxol) and DDP-resistant SKOV-3 (SKOV-3/DDP) cells. HOXB4 knockdown enhanced the cytotoxic effects of Taxol and DDP in A2780/Taxol and SKOV-3/DDP cells, respectively. HOXB4 silencing suppressed the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and reduced the expression of ABCB1, ABCC1 and ABCG2 in ovarian cancer cells. PI3K inhibitor LY294002 or siRNA targeting Akt (si-Akt) treatment inhibited cell viability, decreased protein levels of ABCB1, ABCC1 and ABCG2, and increased LDH release in A2780/Taxol and SKOV-3/DDP cells. These findings revealed that HOXB4 knockdown enhanced the cytotoxic effects of Taxol and DDP by downregulating ABC transporters via inhibiting the PI3K/Akt pathway in ovarian cancer cells.
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PMID:HOXB4 knockdown enhances the cytotoxic effect of paclitaxel and cisplatin by downregulating ABC transporters in ovarian cancer cells. 2966 May 18