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)

Paclitaxel (Taxol) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This appears to involve the overexpression of the drug transporter P-glycoprotein which can efflux both drugs from tumor cells. However, MCF-7ADR cells possess a deletion mutation in p53 and have considerably reduced levels of the Fas receptor, Fas ligand, caspase-2, caspase-6, and caspase-8, suggesting that paclitaxel resistance may also stem from a bona fide block in paclitaxel-induced apoptosis in these cells. To address this issue, we examined the ability of the P-glycoprotein inhibitor valspodar to restore paclitaxel accumulation, paclitaxel cytotoxicity, and paclitaxel-induced apoptosis. Compared to drug sensitive MCF-7 cells, MCF-7ADR cells accumulated >6-fold less paclitaxel, were approximately 100-fold more resistant to killing by the drug, and were highly resistant to paclitaxel-induced apoptosis. In contrast, MCF-7ADR cells pretreated with valspodar were indistinguishable from drug-sensitive cells in their ability to accumulate paclitaxel, in their chemosensitivity to the drug, and in their ability to undergo paclitaxel-induced apoptosis. Valspodar, by itself, did not affect these parameters. This suggests that the enhancement of paclitaxel toxicity in MCF-7ADR cells involves a restoration of apoptosis and not solely through enhanced drug-induced necrosis. Morever, it appears that changes in the levels/activity of p53, the Fas receptor, Fas ligand, caspase-2, caspase-6, or caspase-8 activity have little effect on paclitaxel-induced cytotoxicity and apoptosis in human breast cancer cells.
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PMID:Role of specific apoptotic pathways in the restoration of paclitaxel-induced apoptosis by valspodar in doxorubicin-resistant MCF-7 breast cancer cells. 1083 93

Previous studies by our laboratory have shown that the drug transporter protein P-glycoprotein, P-gp, can specifically inhibit Fas-induced caspase-3 activation and apoptosis. Importantly, inhibition of both caspase-3 activation and cell death could be reversed by pharmacological and antibody inhibitors of P-gp function. However, the molecular mechanisms underpinning P-gp-mediated resistance to Fas-induced cell death and caspase activation remained unknown. We therefore sought to identify the point(s) within the death receptor pathway at which P-gp exerted its inhibitory effect and to determine whether the ATPase activity of P-gp was required. Structure-function analysis determined that ATP hydrolysis was necessary for P-gp to confer resistance to Fas-induced caspase activation and cell death. Importantly, although both FADD and caspase-8 were recruited to the Death Inducing Signal Complex (DISC) in wild-type P-gp expressing cells following Fas ligation, subsequent activation of caspase-8 at the DISC was inhibited. The ability of P-gp to inhibit caspase-8 activation was also ATP dependent. These studies demonstrate that P-gp inhibits Fas-induced caspase-8 activation but not formation of the DISC and that this activity of P-gp is dependent on ATP hydrolysis.
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PMID:P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following Fas ligation. 1240 26

P-glycoprotein (Pgp) is a membrane transporter responsible for resistance to chemotherapy in cancer cells. Its presence in T cells is very well documented, but its function in the immune system is still poorly understood. Recent findings suggest that Pgp may be involved in regulating programmed cell death by inhibiting caspase 8 and caspase 3. Utilising antigenically-activated T cells and the physiologically relevant apoptotic ligand, membrane CD95-L, we have previously reported that while T cells are generally resistant to CD95-induced death at early stages of activation, their susceptibility to apoptosis increases with successive activation and clonal expansion. In this study we investigated whether changes in apoptotic susceptibility were related to T cell Pgp function. Results showed that Pgp expression and function in T cells decreases with maturation, with CD8 cells having the highest Pgp function. However, although Pgp function inversely correlated with caspase 3 activity, no difference was observed between apoptotic susceptible CD25- cells and resistant CD25+ cells. In addition sorting of cells with high and low Pgp function showed no correlation with apoptotic capability. Therefore, whilst Pgp modulates caspase activity, it is not responsible for resistance to apoptosis of early activated T cells nor the increased susceptibility observed at the later stages of maturation in antigenically activated cells.
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PMID:P-glycoprotein decreases with T cell maturation but is not responsible for resistance to CD95-induced apoptosis. 1295 52

The multidrug resistance (MDR) phenotype, induced by the overexpression of several ABC transporters or by antiapoptotic mechanisms, has been identified as the major cause of drug resistance in the treatment of patients with acute myeloid leukemia (AML). In this study, we have shown that valproic acid (VPA) (a histone deacetylase inhibitor) can inhibit the proliferation of both P-glycoprotein (P-gp)- and MDR-associated protein 1 (MRP1)-positive and -negative cells. VPA also induced apoptosis of P-gp-positive cells. VPA induced apoptosis in K562 cells led to decrease in Flip (FLICE/caspase-8 inhibitory protein) expression with Flip cleavage, which could not be observed in HL60 cells. In HL60/MRP cell line, which proved to be resistant to apoptosis by VPA, we observed an abnormal expression of apoptotic regulatory proteins, overexpression of Bcl-2 and absence of Bax. Also, the Bcl-2 antagonist HA14-1 rapidly restored apoptosis in this cell line. Cotreatment with cytosine arabinoside induced very strong apoptosis in both K562/DOX and HL60/DNR cell lines. VPA also induced apoptosis in AML patient cells expressing P-gp and/or MRP1. Our findings show VPA as an interesting drug that should be tested in clinical trials for overcoming the MDR phenotype in AML patients.
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PMID:Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1. 1511 23

The dose-dependent cardiotoxicities of doxorubicin (DOX) significantly limits its anti-cancer efficacies. One of the ways to augment the efficacies of DOX at a relatively low cumulative dose is to use a chemical sensitizer. Here, we demonstrated that schisandrin B (Sch B) significantly enhanced DOX-induced apoptosis of SMMC7721, a human hepatic carcinoma cell line, and of MCF-7, a human breast cancer cell line. This enhancement was irrelevant to the action of Sch B on P-glycoprotein or other drug-transporters, but associated with the activation of caspase-9 rather than caspase-8. The loss of mitochondria membrane potential was observed when cells were treated with DOX and Sch B combined. On the other hand, at the same experimental conditions, Sch B did not enhance the DOX-induced apoptosis of primary rat cardiomyocytes and primary human fibroblasts. Therefore, it is speculative that Sch B may bring benefit to clinical chemotherapy by reducing significantly the cumulative doses of DOX and its associated cardiotoxicities.
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PMID:Schisandrin B enhances doxorubicin-induced apoptosis of cancer cells but not normal cells. 1640 22

Silurus asotus (catfish) egg lectin (SAL) has potent affinity to Gal alpha-linked carbohydrate chains of not only glycoproteins but also glycosphingolipids such as globotriaosylceramide (Gb3). SAL selectively bound to Gb3 localized in glycosphingolipid-enriched microdomain (GEM) of Gb3-expressing (Gb3(+)) Burkitt's lymphoma cells. Since treatment of Gb3(+) cells with SAL caused an increase in externalization of phosphatidylserine via activation of P-glycoprotein, and apoptotic volume decrease via activation of G-protein activated K(+) channel-1, SAL may function as an inducer of early apoptotic signal; however, neither caspase-8 and -3 activation nor DNA fragmentation was observed. We therefore investigated whether cell proliferation and viability were altered in SAL-treated Raji cells. SAL caused reduction of Raji cell proliferation without cytotoxicity. Although SAL did not induce apoptotic cell death to Gb3-expressing cells, it functionally behaved as a regulator of cell proliferation. SAL activated the suppression system of cell proliferation, such as down-regulation of c-myc and cdk4, and up-regulation of p21 and p27, inducing G1 arrest of the cell cycle, and consequently inhibited cell proliferation of Raji cells. Therefore, we conclude that SAL leads the cells to early apoptotic status but not late apoptotic (necrotic) status via binding to Gb3 existing in GEM, and that this binding is a prerequisite condition to induce cell cycle stop signal.
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PMID:[Regulation of globotriaosylceramide (Gb3)-mediated signal transduction by rhamnose-binding lectin]. 1740 83

Cancer chemotherapeutic agents that interfere with tubulin/microtubule function are in extensive use. Quinolone is a common structure in alkaloids and its related components exhibit several pharmacological activities. In this study, we have identified the anticancer mechanisms of 2-phenyl-4-quinolone. 2-Phenyl-4-quinolone displayed anti-proliferative effect in several cancer types, including hormone-resistant prostate cancer PC-3, hepatocellular carcinoma Hep3B and HepG2, non-small cell lung cancer A549 and P-glycoprotein-rich breast cancer NCI/ADR-RES cells. The IC(50) values were 0.85, 1.81, 3.32, 0.90 and 1.53 microM, respectively. 2-Phenyl-4-quinolone caused G2/M arrest of the cell-cycle and a subsequent apoptosis. The turbidity assay showed an inhibitory effect on tubulin polymerization. After immunochemical examination, the data demonstrated that the microtubules were arranged irregularly into dipolarity showing prometaphase-like states. Furthermore, 2-Phenyl-4-quinolone induced the Mcl-1 cleavage, the phosphorylation of Bcl-2 and Bcl-xL (12-h treatment), and the caspase activation including caspase-8, -2 and -3 (24-h treatment). The exposure of cells to 2-phenyl-4-quinolone caused Cdk1 activation by several observations, namely (i) elevation of cyclin B1 expression, (ii) dephosphorylation on inhibitory Tyr-15 of Cdk1, and (iii) dephosphorylation on Ser-216 of Cdc25c. Moreover, a long-term treatment (36h) caused the release reaction and subsequent nuclear translocation of AIF. In summary, it is suggested that 2-phenyl-4-quinolone displays anticancer effect through the dysregulation of mitotic spindles and induction of mitotic arrest. Furthermore, participation of cell-cycle regulators, Bcl-2 family of proteins, activation of caspases and release of AIF may mutually cross-regulate the apoptotic signaling cascades induced by 2-phenyl-4-quinolone.
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PMID:Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways. 1747 21

Multimodal therapies play important roles in the treatment of osteosarcoma (OS) and Ewing's family of tumors (EFTs), two most frequent malignant bone tumors. Although the clinical outcome of primary OS and EFTs is greatly improved, the relapsed cases often are associated with multidrug resistance of the tumors and the prognosis of these patients is still poor. Flavopiridol, a pan cyclin-dependent kinase (CDK) inhibitor is a novel antitumor agent that can induce cell cycle arrest and apoptosis in many cancer cells. However, there have been no studies about the effects of flavopiridol on drug-resistant OS and EFTs. Here, we demonstrated that flavopiridol induced the cleavage of poly-ADP-ribose polymerase (PARP) in a time and dose dependent manner in adriamycin-resistant OS and EFTs cells expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP(1)) as effectively as in their parental cells. Our data also showed that flavopiridol caused the release of mitochondrial cytochrome c and the activation of caspase-9, caspase-8 and caspase-3, with an increase ratio of the proapoptotic protein level (Bax) to the antiapoptotic protein level (Bcl-2 and Bcl-X(L)), while apoptosis was inhibited by pan caspase inhibitor (Z-VAD-FMK) and caspase-3 inhibitor (Z-DEVD-FMK), not by caspase-8 inhibitor (Z-IETD-FMK). The treatment with flavopiridol further inhibited the tumor growth in mouse models of the drug-resistant OS and EFTs. These results suggest that flavopiridol might be promising in clinical therapy for the relapsed OS and EFTs.
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PMID:Cyclin-dependent kinase inhibitor, flavopiridol, induces apoptosis and inhibits tumor growth in drug-resistant osteosarcoma and Ewing's family tumor cells. 1752 Jun 76

EWS-Fli1 plays important roles in oncogenesis of Ewing's family tumors (EFTs). We have reported that EWS-Fli1 inhibits p21(waf1/cip1) and p27(kip1) expressions, which are degraded by the ubiquitin-proteasome pathway. Bortezomib efficiently up-regulated p21(waf1/cip1) and p27(kip1) expression, and induced apoptosis accompanied by the expression of cleaved-PARP, DR4 and activated caspase-8 in EFT cells. Since most EFTs deaths result from the tumor being resistant to chemotherapeutic drugs, the effects of novel anti-tumor reagents on drug-resistant tumors were next investigated. The results demonstrated that the drug-resistant EFT clones were cross-resistant to bortezomib probably due to the over-expression of the efflux pumps, P-glycoprotein and MRP1. We further investigated whether the efflux pump inhibitors would modulate the effects of bortezomib. The combination of P-gp-specific or MRP1-specific inhibitors could enhance the anti-tumor effects of bortezomib on the drug-resistant clones. These data suggest that bortezomib might be a substrate of P-gp and MRP1. Although bortezomib would be effective on the primary EFTs, it is necessary to pay attention to the resistance to bortezomib in clinical trials for the advanced cases. The combination of bortezomib and the efflux pump inhibitors might be a promising method as a novel molecular target therapy for advanced EFTs.
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PMID:The mechanism of cross-resistance to proteasome inhibitor bortezomib and overcoming resistance in Ewing's family tumor cells. 1778 11

Many anthracene derivatives possess excellent anti-tumour activity and are extensively used clinically as anti-tumour agents. However, their clinical use is frequently limited by emergence of multidrug resistance (MDR) in tumour cells. Therefore, new agents with the ability to overcome MDR are needed for cancer treatment. HL-37, a novel anthracene derivative, exhibited potent anti-cancer activity in both drug-sensitive (K562) and multidrug-resistant (K562/DOX) leukaemia cells. Mechanistically, we found that HL-37 was neither a substrate nor an inhibitor of P-glycoprotein (P-gp) and could overcome apoptotic resistance via up-regulation of p53 protein and down-regulation of Bcl-xL protein. In addition, HL-37 also induced K562/DOX cell apoptosis and a decrease in G(0)/G(1) phase. Moreover, reduction of mitochondrial membrane potential, release of cytochrome c and an increased expression of cleaved protein fragment of caspase-3, caspase-9 and caspase-8 were also observed. Importantly, HL-37 was found to be better tolerated and more effective at inhibiting tumour growth than bisantrene in a xenograft mouse model.
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PMID:Anti-tumour effects of HL-37, a novel anthracene derivative, in-vivo and in-vitro. 1823 69


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