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)

P-glycoprotein (P-gp), a plasma membrane pump associated with multidrug resistance (MDR), is a member of the superfamily of ATP-binding cassette (ABC) transporters. The discovery that inhibitors of drug efflux can increase drug accumulation and reverse drug resistance in the laboratory has led to the clinical development of a number of P-gp inhibitors. Initial studies were performed with agents already in use in the clinic for other indications, the 'first generation' studies. Second generation inhibitors were taken into clinical trials in leukemia, breast cancer, ovarian cancer and sarcoma, malignancies for which there is evidence that P-gp is expressed, and in some cases, associated with a poorer therapeutic outcome. One major limitation of these trials, however, was the reduction in anticancer drug doses that was required with concurrent administration of inhibitor. The reduction in drug dose needed in these combination studies, may have confounded the results and contributed to disappointing outcomes. Functional assays to verify the role of P-gp inhibition in MDR, such as sestamibi imaging are proving helpful in assessing the development of improved inhibitors that are providing hope for the future. This review focuses on attempts aimed at overcoming resistancemediated by ABC transporters and evaluates the prospects for addition of new inhibitors to the anticancer armamentarium.
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PMID:ABC transporters and inhibitors: new targets, new agents. 1247 69

Gemcitabine (2',2'-difluorodeoxycytidine) is a deoxycytidine analogue that is activated by deoxycytidine kinase (dCK) to its monophosphate and subsequently to its triphosphate dFdCTP, which is incorporated into both RNA and DNA, leading to DNA damage. Multidrug resistance (MDR) is characterised by an overexpression of the membrane efflux pumps P-glycoprotein (P-gP) or multidrug resistance-associated protein (MRP). Gemcitabine was tested against human melanoma, non-small-cell lung cancer, small-cell lung cancer, epidermoid carcinoma and ovarian cancer cells with an MDR phenotype as a result of selection by drug exposure or by transfection with the mdr1 gene. These cell lines were nine- to 72-fold more sensitive to gemcitabine than their parental cell lines. The doxorubicin-resistant cells 2R120 (MRP1) and 2R160 (P-gP) were nine- and 28-fold more sensitive to gemcitabine than their parental SW1573 cells, respectively (P<0.01), which was completely reverted by 25 micro M verapamil. In 2R120 and 2R160 cells, dCK activities were seven- and four-fold higher than in SW1573, respectively, which was associated with an increased dCK mRNA and dCK protein. Inactivation by deoxycytidine deaminase was 2.9- and 2.2-fold decreased in 2R120 and 2R160, respectively. dFdCTP accumulation was similar in SW1573 and its MDR variants after 24 h exposure to 0.1 micro M gemcitabine, but dFdCTP was retained longer in 2R120 (P<0.001) and 2R160 (P<0.003) cells. 2R120 and 2R160 cells also incorporated four- and six-fold more [(3)H]gemcitabine into DNA (P<0.05), respectively. P-glycoprotein and MRP1 overexpression possibly caused a cellular stress resulting in increased gemcitabine metabolism and sensitivity, while reversal of collateral gemcitabine sensitivity by verapamil also suggests a direct relation between the presence of membrane efflux pumps and gemcitabine sensitivity.
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PMID:Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines. 1279 44

The taxanes, paclitaxel (PTX) and docetaxel (DTX), belong to a novel class of anticancer drugs that stabilize microtubules and lead to tumor cell death. While both agents are widely used for the treatment of lung, breast, and ovarian cancer, many tumor types are refractory or develop resistance to these drugs. We describe here a novel analogue of DTX, designated MAC-321 [Microtubule/Apoptosis/Cytotoxic: 5beta, 20-epoxy-1, 2alpha-, 4-, 7beta-, 10beta-, 13alpha-hexahydroxytax-11-en-9-one 4 acetate 2 benzoate 7-propionate 13-ester with (2R,3S)-N-tertbutoxycarbonyl-3-(2-furyl)isoserine], that overcomes P-glycoprotein-mediated resistance to PTX and DTX in preclinical model systems. Similar to PTX or DTX, MAC-321 enhanced the rate of tubulin polymerization in vitro and caused the bundling of microtubules in cells. MAC-321 inhibited proliferation of a panel of 14 tumor cell lines with minimal variation in potency (IC(50) = 2.2 +/- 1.4 nM; range = 0.6-5.3 nM). Unlike PTX or DTX, the IC(50) of MAC-321 did not vary in cells that expressed low to moderate levels of P-glycoprotein. Even under extraordinary conditions in KB-V1 cells, which highly overexpress P-glycoprotein, resistance to MAC-321 was 80-fold compared with that of PTX (1400-fold) and DTX (670-fold). In addition, equivalent or less resistance to MAC-321 compared with PTX or DTX was observed in four cell lines that contain distinct point mutations within the taxane-binding site of beta-tubulin. Most importantly, MAC-321 displayed superior in vivo efficacy because: (a) MAC-321 either partially or completely inhibited tumor growth in three tumor models that overexpressed P-glycoprotein and were resistant to PTX; and (b) unlike PTX or DTX, MAC-321 was highly effective when given orally. MAC-321 was also highly effective when given as single i.v. dose. Our findings suggest that MAC-321, which is currently under clinical evaluation, may have broad therapeutic value.
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PMID:MAC-321, a novel taxane with greater efficacy than paclitaxel and docetaxel in vitro and in vivo. 1455 6

High glucosylceramide synthase (GCS) activity is one factor contributing to multidrug resistance (MDR) in breast cancer. Enforced GCS overexpression has been shown to disrupt ceramide-induced apoptosis and to confer resistance to doxorubicin. To examine whether GCS is a target for cancer therapy, we have designed and tested the effects of antisense oligodeoxyribonucleotides (ODNs) to GCS on gene expression and chemosensitivity in multidrug-resistant cancer cells. Here, we demonstrate that antisense GCS (asGCS) ODN-7 blocked cellular GCS expression and selectively increased the cytotoxicity of anticancer agents. Pretreatment with asGCS ODN-7 increased doxorubicin sensitivity by 17-fold in MCF-7-AdrR (doxorubicin-resistant) breast cancer cells and by 10-fold in A2780-AD (doxorubicin-resistant) ovarian cancer cells. In MCF-7 drug-sensitive breast cancer cells, asGCS ODN-7 only increased doxorubicin sensitivity by 3-fold, and it did not influence doxorubicin cytotoxicity in normal human mammary epithelial cells. asGCS ODN-7 was shown to be more efficient in reversing drug resistance than either the GCS chemical inhibitor d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol or the P-glycoprotein blocking agents verapamil and cyclosporin A. Experiments defining drug transport and lipid metabolism parameters showed that asGCS ODN-7 overcomes drug resistance mainly by enhancing drug uptake and ceramide-induced apoptosis. This study demonstrates that a 20-mer asGCS oligonucleotide effectively reverses MDR in human cancer cells.
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PMID:Oligonucleotides blocking glucosylceramide synthase expression selectively reverse drug resistance in cancer cells. 1496 19

Paclitaxel (PTX) is a potent anti-neoplastic agent that is highly effective in treating ovarian cancer. Nevertheless, the emergence of PTX resistance has limited the control of this disease. To gain insight into the molecular alterations accompanying drug resistance in ovarian cancer, we generated a new stable PTX-resistant ovarian carcinoma cell line. CABA I cells, which display an intrinsic PTX resistance (IC50 = 800 ng/ml), were subjected to continuous exposure to PTX. From the residual surviving cells, the highly PTX-resistant line CABA-PTX (IC50 = 256000 ng/ml) was generated and stably maintained in vitro. Analysis of beta-tubulin expression indicated that only the HM40 and Hbeta9 isotypes were expressed in both parental and resistant cells. No specific point mutations in the HM40 were detected in either cell line, but expression levels of this isotype were significantly reduced (40%) in CABA-PTX cells. Hbeta9 levels were unchanged. In those cells, PTX resistance was associated with cross-resistance to vinblastine but not to methotrexate or 5-fluorouracil. Verapamil treatment did not reverse the intrinsic drug resistance of parental cells, but partially modulated the sensitivity of CABA-PTX cells to PTX and induced total sensitivity to vinblastine. No changes in the cell surface expression of the drug efflux pumps MRP1, MRP2 and P-glycoprotein were observed. PTX influx, monitored using a fluorescent drug derivative, was significantly reduced and delayed in CABA-PTX cells as compared to the parental cells. Together, these findings suggest that more than one mechanism is involved in PTX resistance, making CABA-PTX cell line a potentially valuable in vitro tool to study multifactorial acquired drug resistance in ovarian cancer.
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PMID:Induction of a multifactorial resistance phenotype by high paclitaxel selective pressure in a human ovarian carcinoma cell line. 1514 55

Drug resistance, in particular multidrug resistance, is a serious problem that impedes the effectiveness of chemotherapy. Multidrug resistance results mainly from an enhanced efflux of drugs by drug pumps located on the cell membrane such as P-glycoprotein. In the study reported here we showed that EM012, a microtubule-interfering agent, is a weak substrate for P-glycoprotein and inhibited the proliferation of A2780/ADR human ovarian cancer cells, which possess multidrug resistance due to P-glycoprotein overexpression. A2780/ADR cells treated with EM012 exhibited pronounced mitotic arrest, developed large multilobed nuclei, and eventually died through the initiation of apoptosis. Intraperitoneal treatment of A2780/ADR xenograft tumors in athymic nude mice with EM012 significantly inhibited tumor progression through triggering apoptosis and conferred an apparent survival advantage. Furthermore, EM012 treatment did not cause detectable toxicity to normal tissues. These findings suggest that EM012 may serve as a novel chemotherapeutic agent for the treatment of multidrug-resistant human ovarian cancer.
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PMID:EM012, a microtubule-interfering agent, inhibits the progression of multidrug-resistant human ovarian cancer both in cultured cells and in athymic nude mice. 1569 Feb 3

Cancer Research UK has recently sponsored a meeting, organized by the UK Medical Research Council, on cancer drug resistance. Several of the molecular mechanisms responsible for this clinical outcome, such as DNA interstrand crosslink repair, apoptosis evasion, cytochrome P450 and P-glycoprotein, were discussed. There was a special focus on leukaemia, breast and ovarian cancer, and the potential use of positron-emission tomography to study anticancer-drug resistance. The progress made in translating these findings to the clinic, like Gefitinib, P-glycoprotein phenotyping, or genome-wide analysis technology, was also discussed.
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PMID:Drug resistance in cancer. 1623 20

Aplidin-resistant IGROV-1/APL cells were derived from the human ovarian cancer IGROV-1 cell line by exposing the cells to increasing concentration of Aplidin for eight months, starting from a concentration of 10 nM to a final concentration of 4 microM. IGROV-1/APL cell line possesses five fold relative resistance to Aplidin. IGROV-1/APL resistant cell line shows the typical MDR phenotype: (1) increased expression of membrane-associated P-glycoprotein, (2) cross-resistance to drugs like etoposide, doxorubicin, vinblastine, vincristine, taxol, colchicin and the novel anticancer drug Yondelis (ET-743). The Pgp inhibitor cyclosporin-A restored the sensitivity of IGROV-1/APL cells to Aplidin by increasing the drug intracellular concentration. The resistance to Aplidin was not due to the other proteins, such as LPR-1 and MRP-1, being expressed at the same level in resistant and parental cell line. The finding that cells over-expressing Pgp are resistant to Aplidin was confirmed in CEM/VLB 100 cells, that was found to be 5-fold resistant to Aplidin compared to the CEM parental cell line.
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PMID:Induction of resistance to Aplidin in a human ovarian cancer cell line related to MDR expression. 1625 64

The aim of the study was to determine if biomarker expression could help discriminate between short-term and long-term survivors in women with advanced ovarian cancer. Fifty-one patients with stage III ovarian cancer were selected for the study, which included 28 short-term survivors (death from ovarian cancer within 18 months) and 23 long-term survivors (alive for more than 5 years). There was no difference between the two groups with respect to FIGO substage, age, World Health Organization score, and first-line platinum therapy. Classic clinical pathologic parameters were examined together with p53, Bcl-2, Ki-67, PDGFRalpha, P-glycoprotein, BRCA1, and DNA ploidy. Immunohistochemistry was used for scoring biomarker expression and image cytometry for DNA ploidy. All patients had primary debulking surgery followed by first-line platinum therapy. On multivariate analysis, the presence of ascites, debulking surgery and repeat laparotomy, clear-cell histology, elevated CA125, and high Ki-67 score were all found to be of prognostic importance. The long-term survivors were characterized by primary optimal cytoreduction surgery (<1 cm residual disease), attempt at maximal tumor debulking by experienced gynecological oncologic surgeons, and the absence of ascites. Normal CA125 level before platinum therapy and negative Ki-67 expression also predicted a more favorable prognosis.
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PMID:Prognostic factors in ovarian carcinoma stage III patients. Can biomarkers improve the prediction of short- and long-term survivors? 1634 77

Overexpression of breast cancer resistance protein (BCRP) and mitoxantrone (MX) resistance protein can confer resistance to a variety of cytostatic drugs, such as MX, topotecan (TPT), doxorubicin, and daunorubicin. This study investigates the role of BCRP in resistance of ovarian cancer to TPT treatment. We have developed TPT-resistant human ovarian cancer cell line. Intracellular concentration of fluorescent dye rhodamine 123 (Rh123) was measured by flow cytometry. The expression of several membrane transporter proteins including P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and BCRP were determined by reverse transcription-polymerase chain reaction and Western blotting. The Rh123 concentration in parental cells was approximately three times of those in TPT-resistant cells. In contrast to undetectable level of P-gp messenger RNA (mRNA) and minimal level of MRP1 expression in TPT-resistant cells, overexpression of both the BCRP mRNA and the protein was detected in these cells. Introduction of antisense-phosphorothioate oligonucleotide derived from BCRP mRNA into TPT-resistant cells resulted in a significant increase in the concentration of intracellular Rh123. These results suggested a novel mechanism in which a reduced intracellular drug concentration may be mediated by BCRP gene products in human ovarian cancer cells.
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PMID:Breast cancer resistance protein-mediated topotecan resistance in ovarian cancer cells. 1634 80


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