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)

Indirect evidence has suggested that P-glycoprotein (P-gp), the multidrug transporter, is phosphorylated by protein kinase C (PKC) and that phosphorylation modulates its transport function. To address the first premise more directly, ie., that P-gp is phosphorylated by PKC, we investigated the interaction between P-gp and PKC in sensitive and multidrug resistant MCF-7 and KB human carcinoma cell lines. We found that P-gp and PKC were coimmunoprecipitated from the multidrug-resistant cell lines MCF-7/AdrR and KB-V-1, using antibodies to either protein. The association between the two proteins was enhanced by phorbol 12-myristate 13-acetate, an analogue of diacylglycerol that induces translocation of PKC to the plasma membrane. The anti-P-gp immunoprecipitates contained PKC activity as measured by direct phosphorylation reactions. The interaction of PKC with P-gp displayed isozyme specificity: PKC-alpha, -beta, gamma, -epsilon, and -phi, but not -delta, -mu, -zeta, -lambda, were found to coimmunoprecipitate with P-gp. These studies indicate that P-gp closely interacts with PKC and serves as a substrate, and that specific isozymes of this kinase may be involved in the phosphorylation of the multidrug transporter.
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PMID:Interaction of P-glycoprotein with protein kinase C in human multidrug resistant carcinoma cells. 875 35

One of the major problems in cancer chemotherapy is the development of tumor resistance to drug treatment. In in vitro experiments, the stepwise selection of cancer cells resistant to a single antineoplastic agent may lead to resistance to multiple agents (multidrug resistance). One of the well known mechanisms leading to multidrug resistance is the over-expression of the mdr1 gene product, the 170 kDa membrane P-glycoprotein which is an ATP-driven efflux pump of xenobiotics. We studied the effects of dextran-conjugated doxorubicin in combination with colchicine, vinblastine and free doxorubicin respectively on the killing of human KB 3-1 carcinoma cells and its multidrug resistant subclone KB-V-1 cells. Cell survival was quantified by the tetrazolium salt MTT assay Cytotoxicity studies were designed so that data could be analyzed by the medium-effect principle and the calculated Combination Indices at different cell survival levels. When added alone conjugated doxorubicin was not as effective as doxorubicin in cell killing. When conjugated doxorubicin was combined with free doxorubicin or colchicine at high (over 75%) killing rates, a significant degree of synergism was observed in the killing of multidrug resistant KB-V1 cells. This synergism was not observed in non-resistant KB-3-1 cells nor when conjugated doxorubicin was combined with vinblastine.
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PMID:Partial synergism between dextran-conjugated doxorubicin and cancer drugs on the killing of multidrug resistant KB-V1 cells. 904 56

Resistance to chemotherapy is the major cause of cancer treatment failure. Insight into the mechanism of action of agents that modulate multidrug resistance (MDR) is instrumental for the design of more effective treatment modalities. Here we show, using KB-V-1 MDR human epidermoid carcinoma cells and [3H]palmitic acid as metabolic tracer, that the MDR modulator SDZ PSC 833 (PSC 833) activates ceramide synthesis. In a short time course experiment, ceramide was generated as early as 15 min (40% increase) after the addition of PSC 833 (5.0 microM), and by 3 h, [3H]ceramide was >3-fold that of control cells. A 24-h dose-response experiment showed that at 1.0 and 10 microM PSC 833, ceramide levels were 2.5- and 13.6-fold higher, respectively, than in untreated cells. Concomitant with the increase in cellular ceramide was a progressive decrease in cell survival, suggesting that ceramide elicited a cytotoxic response. Analysis of DNA in cells treated with PSC 833 showed oligonucleosomal DNA fragmentation, characteristic of apoptosis. The inclusion of fumonisin B1, a ceramide synthase inhibitor, blocked PSC 833-induced ceramide generation. Assessment of ceramide mass by TLC lipid charring confirmed that PSC 833 markedly enhanced ceramide synthesis, not only in KB-V-1 cells but also in wild-type KB-3-1 cells. The capacity of PSC 833 to reverse drug resistance was demonstrated with vinblastine. Whereas each agent at a concentration of 1.0 microM reduced cell survival by approximately 20%, when PSC 833 and vinblastine were coadministered, cell viability fell to zero. In parallel experiments measuring ceramide metabolism, it was shown that the PSC 833/vinblastine combination synergistically increased cellular ceramide levels. Vinblastine toxicity, also intensified by PSC 833 in wild-type KB-3-1 cells, was as well accompanied by enhanced ceramide formation. These data demonstrate that PSC 833 has mechanisms of action in addition to P-glycoprotein chemotherapy efflux pumping.
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PMID:SDZ PSC 833, the cyclosporine A analogue and multidrug resistance modulator, activates ceramide synthesis and increases vinblastine sensitivity in drug-sensitive and drug-resistant cancer cells. 1002 79

Anti-psychotic drugs are used in cancer patients undergoing chemotherapy frequently and the concomitantly used drugs may alter the pharmacokinetics of each other. One reason for the alteration of pharmacokinetics may be the modulation of the function of P-glycoprotein, whose efflux pump occurs in resistant cancer cells, in human intestine and in the blood-brain barrier. For this reason we tested the effect of several anti-psychotic drugs on the multidrug-resistant pump, P-glycoprotein. We found that in the MDR gene transfected L121C MDR, L5178 MDR and in the KB-V-1 cells selected for resistance some antipsychotic drugs block the function of P-glycoprotein. Blood cells of two treatment-resistant leukemic patients also showed increased uptake of daunorubicin if treated ex vivo with the anti-psychotic drugs. Our results suggest that pharmacokinetic studies should be performed prior to concomitant clinical use of such drugs which block P-glycoprotein function.
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PMID:Anti-psychotic drugs reverse multidrug resistance of tumor cell lines and human AML cells ex-vivo. 1040 3

Many studies have been performed with the aim of developing effective resistance modulators to overcome the multidrug resistance (MDR) of human cancers. Potent MDR modulators are being investigated in clinical trials. Many current studies are focused on dietary herbs due to the fact that these have been used for centuries without producing any harmful side effects. In this study, the effect of tetrahydrocurcumin (THC) on three ABC drug transporter proteins, P-glycoprotein (P-gp or ABCB1), mitoxantrone resistance protein (MXR or ABCG2) and multidrug resistance protein 1 (MRP1 or ABCC1) was investigated, to assess whether an ultimate metabolite form of curcuminoids (THC) is able to modulate MDR in cancer cells. Two different types of cell lines were used for P-gp study, human cervical carcinoma KB-3-1 (wild type) and KB-V-1 and human breast cancer MCF-7 (wild type) and MCF-7 MDR, whereas, pcDNA3.1 and pcDNA3.1-MRP1 transfected HEK 293 and MXR overexpressing MCF7AdrVp3000 or MCF7FL1000 and its parental MCF-7 were used for MRP1 and MXR study, respectively. We report here for the first time that THC is able to inhibit the function of P-gp, MXR and MRP1. The results of flow cytometry assay indicated that THC is able to inhibit the function of P-gp and thereby significantly increase the accumulation of rhodamine and calcein AM in KB-V-1 cells. The result was confirmed by the effect of THC on [(3)H]-vinblastine accumulation and efflux in MCF-7 and MCF-7MDR. THC significantly increased the accumulation and inhibited the efflux of [(3)H]-vinblastine in MCF-7 MDR in a concentration-dependent manner. This effect was not found in wild type MCF-7 cell line. The interaction of THC with the P-gp molecule was clearly indicated by ATPase assay and photoaffinity labeling of P-gp with transport substrate. THC stimulated P-gp ATPase activity and inhibited the incorporation of [(125)I]-iodoarylazidoprazosin (IAAP) into P-gp in a concentration-dependent manner. The binding of [(125)I]-IAAP to MXR was also inhibited by THC suggesting that THC interacted with drug binding site of the transporter. THC dose dependently inhibited the efflux of mitoxantrone and pheophorbide A from MXR expressing cells (MCF7AdrVp3000 and MCF7FL1000). Similarly with MRP1, the efflux of a fluorescent substrate calcein AM was inhibited effectively by THC thereby the accumulation of calcein was increased in MRP1-HEK 293 and not its parental pcDNA3.1-HEK 293 cells. The MDR reversing properties of THC on P-gp, MRP1, and MXR were determined by MTT assay. THC significantly increased the sensitivity of vinblastine, mitoxantrone and etoposide in drug resistance KB-V-1, MCF7AdrVp3000 and MRP1-HEK 293 cells, respectively. This effect was not found in respective drug sensitive parental cell lines. Taken together, this study clearly showed that THC inhibits the efflux function of P-gp, MXR and MRP1 and it is able to extend the MDR reversing activity of curcuminoids in vivo.
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PMID:Modulation of function of three ABC drug transporters, P-glycoprotein (ABCB1), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCC1) by tetrahydrocurcumin, a major metabolite of curcumin. 1696 Jun 58

Contribution of the ABCB1/MDR1/P-glycoprotein drug transporter to breast cancer resistance has been controversial. One issue is that ABCB1-dependent drug-resistance has primarily been investigated in mammary epithelial cell models technically manipulated to overexpress ABCB1, either by gene transfer using appropriate expression vectors or by chronic anticancer drug-selection. However, an unmodified human breast cancer cell line with an endogenous overexpression of ABCB1 has not been described thus far. Using Affymetrix microarray analyses, we identified an endogenous overexpression of several tumor-biologically relevant transcripts including ABCB1, BCAR4, CCL28, SCGB2A2 and PIP in IPH-926, an anticancer drug-resistant human lobular breast cancer cell line derived from a chemo-refractory mammary carcinoma patient. In a panel of twenty breast cancer cell lines examined, overexpression of ABCB1 mRNA and protein was exclusively detected in IPH-926. This was further validated using chronically in vitro drug-selected KB-V-1 cells as a widely used reference model to accurately define an ABCB1 overexpression. IPH-926 and KB-V-1 displayed a similar overexpression of ABCB1. Flow cytometric analyses showed that IPH-926 but not ABCB1-negative breast cancer cells extruded the anticancer agent doxorubicin, a classical substrate of the ABCB1 drug transporter. PSC-833 (valspodar), a selective ABCB1 inhibitor, blocked this efflux, restored apoptotic PARP cleavage and increased doxorubicin sensitivity in IPH-926 and KB-V-1. To our knowledge, IPH-926 represents the first human breast cancer cell line with a genuine, endogenous overexpression of ABCB1. IPH-926 provides evidence that ABCB1 can occasionally cause anticancer drug-resistance in breast cancer patients and offers a new tool for the evaluation of compounds to overcome drug-resistance.
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PMID:ABCB1/MDR1 contributes to the anticancer drug-resistant phenotype of IPH-926 human lobular breast cancer cells. 2211 13