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)

A human colon carcinoma cell line selected for a 21-fold resistance to mitoxantrone was cross-resistant to the anthracycline, doxorubicin, but not to the anthracene, bisantrene. A 2-fold resistance was observed with vinblastine, another drug associated with multidrug resistance. Net intracellular mitoxantrone and doxorubicin accumulation were decreased at 1 h for all dose levels in the resistant cell line compared to the sensitive cell line. Although the resistant cells were more resistant to mitoxantrone than doxorubicin, the net accumulation of mitoxantrone was only 19% less than the sensitive cell line; whereas doxorubicin accumulation was decreased by 49%. No significant difference between the sensitive and resistant cell lines was observed in the initial accumulation of mitoxantrone; however, the efflux of mitoxantrone was increased in the resistant cell line. Verapamil did not overcome the resistance to mitoxantrone and did not increase the net accumulation of drug. No alterations in the electrophoretic mobility of membrane proteins were observed. Using immunoblotting techniques, the resistant cell line did not express P-glycoprotein which is frequently observed for cells resistant to anthracycline antibiotics. Cytogenetic analysis showed a putative homogenously staining region on the short arm of chromosome 7 in the resistant cell line. The limited cross-resistant phenotype, lack of verapamil reversal, nondetection of P-glycoprotein, and cytogenetic evidence of gene amplification suggests the involvement of a novel drug-resistant gene associated with resistance to mitoxantrone.
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PMID:Cytogenetic and phenotypic analysis of a human colon carcinoma cell line resistant to mitoxantrone. 289 93

A mitomycin C-resistant (MMCR) strain of L1210 mouse leukemia was developed by continuous drug exposure in vitro. MMC concentrations were increased in a stepwise fashion beginning at 0.033 microM and ending at 0.34 microM. This produced a 10-fold resistant cell line over the parental line. Resistance simultaneously developed to anthracene and anthracycline DNA intercalators, to vinca alkaloids and epipodophyllotoxins but not to cisplatin, bleomycin, fluorouracil or ionizing X-rays. MMC resistance was reversed using the membrane-active agent verapamil. The level of non-protein sulfhydryls was increased 2-fold in the MMCR cells. Intracellular uptake of unchanged MMC was reduced by 40% in the MMCR cells. Cytogenetic analyses demonstrated no recognizable clonal chromosomal alterations unique to the resistant subline and no evidence of double minutes or homogeneously staining regions in the DNA. Gel renaturation analysis failed to document the presence of an amplified DNA domain. Southern blotting of parental and MMCR DNA using a cDNA probe (CHP1) for the P-glycoprotein gene also failed to demonstrate amplification or rearrangement of P-glycoprotein-related homologous sequences. However, an Mr 180,000 glycoprotein was detected in the plasma membranes from MMCR cells. This protein also specifically reacted with a monoclonal antibody (C219) to the P-glycoprotein of Ling and co-workers [Kartner et al., Nature, Lond. 316, 820 (1985)]. These results suggest a pleiotropic drug resistance pattern in the MMCR cells, associated with membrane glycoprotein alterations, enhanced non-protein sulfhydryl levels, and reduced MMC accumulation. This is a novel observation for a resistant cell line selected with an alkylating agent.
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PMID:Mitomycin C resistant L1210 leukemia cells: association with pleiotropic drug resistance. 311 61

Bisantrene, mitoxantrone, and anthracyclines are anthracene derivatives that interact with DNA and are used for the treatment of cancers. The mechanisms of resistance to bisantrene are unknown. Here we show that cells that overexpress low levels of P-glycoprotein or are transfected with human MDR1 have approximately 10-fold greater resistance to bisantrene compared to vinblastine, doxorubicin, or colchicine. Furthermore, bisantrene can be used to select for high-level P-glycoprotein-mediated multiple drug resistance in a human colon carcinoma cell line, LS 174T, and the drug blocks photoaffinity labeling of P-glycoprotein. The data suggest that bisantrene is an excellent substrate for P-glycoprotein. These findings could influence subsequent clinical evaluation of bisantrene for the treatment of cancer.
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PMID:P-glycoprotein mediates profound resistance to bisantrene. 786 4

We used a series of P-glycoprotein (P-gp) expressing multidrug-resistant (MDR) cells, developed from human breast cancer MCF-7 cells by exposure to Adriamycin, to investigate the effects of flavonoids on P-gp-mediated efflux mechanisms for chemical carcinogens. We previously showed that MDR cells derived from exposure to Adriamycin are cross-resistant to a chemical carcinogen, benzo(a)pyrene, due to its cellular efflux by the P-gp-mediated putative drug efflux pump. Our current studies extended this observation to another polycyclic aromatic hydrocarbon, 7,12-dimethylbenz(a)anthracene, known to induce mammary tumors in animals. In our attempt to find naturally occurring dietary compounds which may stimulate the P-gp-mediated efflux of carcinogens, we found that certain flavonols, kaempferol, quercetin, and galangin, are potent stimulators of the P-gp-mediated efflux of 7,12-dimethylbenz(a)-anthracene. The increased efflux decreased the cellular burden of 7,12-dimethylbenz(a)anthracene. Since these flavonol compounds are widely distributed in fruits and vegetables, their stimulatory effect on P-gp may be a mechanism relevant to carcinogenesis and the observed lowered cancer risk in humans with higher dietary intake of fruits and vegetables.
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PMID:Flavonol-stimulated efflux of 7,12-dimethylbenz(a)anthracene in multidrug-resistant breast cancer cells. 790 98

The constitutive and induced activities of cytochrome P-4501A isoforms in hepatoma McA 7777 sublines with different levels of colchicine (CH) resistance were studied. The higher CH resistance was associated with the elevated functional activity of P-glycoprotein (Pgp). The constitutive level of benzo(a)pyrene hydroxylase and 7-ethoxyresorufin O-deethylase (cytochrome P-4501A-dependent activities) were the same in sublines with different CH resistance levels. However, benzo(a)-anthracene, a cytochrome P-4501A inducing agent, more effectively induced benzo(a)pyrene hydroxylase and 7-ethoxyresorufin O-deethylase activities in sublines with elevated P-glycoprotein activity. The toxicity of benzo(a)pyrene, a compound which is simultaneously a cytochrome P-4501A-inducing agent and a toxic agent activated by cytochrome P-4501A, is more effective in sublines with elevated CH resistance. These results support the suggestion about the coordinated regulation of enzyme systems involved in the defence against various lipophilic xenobiotics. The possibility to overcome the Pgp-mediated MDR of some tumours by using a combination of some drugs including compounds which induce the cytochrome P-4501A isoforms and are activated by them is discussed.
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PMID:Coordinated regulation of P-glycoprotein activity and cytochrome P-4501A induction in sublines of rat hepatoma McA RH7777 cells with different levels of colchicine resistance. 1036 66

Rat liver epithelial cells resistant to the chemical carcinogen 3MC, termed F258/3MC cells and generated by long-term exposure of parental F258 cells to the PAH, were characterized, especially with respect to expression of multidrug resistance transporters such as P-glycoprotein, MRP1 and MRP2. F258/3MC cells were found to be cross-resistant to other PAHs such as BP and dimethylbenz(a)anthracene but remained sensitive to known substrates of multidrug resistance efflux pumps such as doxorubicin and vincristine. They did not display either decreased cellular PAH accumulation or increased PAH efflux. In addition, P-glycoprotein and MRP2 mRNA levels were not, or only barely detected, in F258/3MC cells and in their parental counterparts whereas these PAH-resistant and sensitive cells showed closed levels of MRP1 mRNAs and activity. Moreover, P-gp- and MRP1-overexpressing cells were shown to display similar accumulation and efflux of BP than those found in P-gp- and MRP1-negative control cells. These data therefore suggest that multidrug resistance transporters do not contribute to PAH resistance in PAH-selected liver cells.
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PMID:Unaltered expression of multidrug resistance transporters in polycyclic aromatic hydrocarbon-resistant rat liver cells. 1116 13

Resistance to chemotherapeutic agent is a major cause of treatment failure in patients with cancer. In many cases, the primaly mechanism leading to a multidrug-resistant phenotype is the plasma-membrane localized overexpression of drug efflux transporters, such as P-glycoprotein. However, acidic intracellular organelles seem also to participate in resistance to chemotherapeutic drugs and the determination of the pH of these organelles is of importance. In the present study we have used a new fluorescent derivative of verapamil, 2-2-diphenyl-5-[(methylaminomethyl)anthracene] pentanenitrile (EDP 96), and show that it is an efficient inhibitor of the P-gp-mediated efflux of anthracycline in K562 resistant cells. The fluorescence of EDP 96 is environmental and pH sensitive. EDP 96 is a weak base (pKa=6.0) and its accumulation into K562 cells is accompanied by a significant fluorescence increase due to its entry of the drug into acidic regions in the cells. We have used this properties to develop a new method to accurately determine the pH of acidic organelle.
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PMID:Fluorescent verapamil analogue for monitoring acidic intracellular organelles in multidrug resistant and sensitive cells. 1151 60

Anthracene-1,4-dione and 6,7-dichloro-1,4-anthracenedione (code names AQ1 and AQ4, respectively) are cytostatic (IC50: 53 and 110 nM, respectively) and cytotoxic (IC50: 100 and 175 nM, respectively) in wild-type drug-sensitive HL-60-S tumor cells at day 4 in vitro. Therefore, the antitumor effects of these drugs were assessed and compared to those of daunorubicin (DAU) in HL-60-RV and HL-60-R8 tumor cells, which are, respectively, P-glycoprotein-positive and -negative multidrug-resistant (MDR) sublines. In contrast to DAU, which loses its cytostatic [resistance factors (RFs): 30.3-31.8] and cytotoxic (RFs: 48.8-58.1) activities in MDR sublines, AQ1 inhibits cell proliferation (RFs: 0.9-1.3) and cell viability (RFs: 1.4-1.6) as effectively in HL-60-RV and HL-60-R8 as in HL-60-S cells. Similarly, DAU decreases the rate of DNA synthesis less effectively in MDR sublines (RFs: 8.0-13.3) but AQ1 inhibits the incorporation of [3H]thymidine into DNA to the same degree in HL-60-S as in HL-60-RV and HL-60-R8 cells (RFs: 0.9-1.1). In contrast to DAU, which is ineffective, the advantage of AQ1 is its ability to block the cellular transport of purine and pyrimidine nucleosides in HL-60-S cells, an effect which persists in the MDR sublines (RFs: 1.1). AQ4, which mimics to a lesser degree all the antitumor effects of AQ1, except the inhibition of adenosine transport, also retains its effectiveness in MDR sublines (RFs: 1.1-3.1). The peaks of DNA cleavage caused by DAU and AQ1 in HL-60-S cells shift to lower concentrations with increasing times of drug exposure but DAU loses most of its ability to induce DNA fragmentation in MDR sublines, whereas the levels of AQ1-induced DNA cleavage at 16 and 24 h are nearly equivalent in HL-60-S, HL-60-RV and HL-60-R8 cells. Because they not only mimic the antitumor effects of DAU in the nM range but also block nucleoside transport and remain effective in tumor cells that have developed different mechanisms of MDR, AQ1 and AQ4 analogs might be valuable to develop new means of polychemotherapy.
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PMID:Synthetic 1,4-anthracenediones, which block nucleoside transport and induce DNA fragmentation, retain their cytotoxic efficacy in daunorubicin-resistant HL-60 cell lines. 1170 48

P-glycoprotein (Pgp) is a 170 kDa phosphorylated glycoprotein encoded by human MDR1 gene. It is responsible for the systemic disposition of numerous structurally and pharmacologically unrelated lipophilic and amphipathic drugs, carcinogens, toxins, and other xenobiotics in many organs, such as the intestine, liver, kidney, and brain. Like cytochrome P450s (CYP3A4), Pgp is vulnerable to inhibition, activation, or induction by herbal constituents. This was demonstrated by using an ATPase assay, purified Pgp protein or intact Pgp-expressing cells, and proper probe substrates and inhibitors. Curcumin, ginsenosides, piperine, some catechins from green tea, and silymarin from milk thistle were found to be inhibitors of Pgp, while some catechins from green tea increased Pgp-mediated drug transport by heterotropic allosteric mechanism, and St. John's wort induced the intestinal expression of Pgp in vitro and in vivo. Some components (e.g., bergamottin and quercetin) from grapefruit juice were reported to modulate Pgp activity. Many of these herbal constituents, in particular flavonoids, were reported to modulate Pgp by directly interacting with the vicinal ATP-binding site, the steroid-binding site, or the substrate-binding site. Some herbal constituents (e.g., hyperforin and kava) were shown to activate pregnane X receptor, an orphan nuclear receptor acting as a key regulator of MDR1 and many other genes. The inhibition of Pgp by herbal constituents may provide a novel approach for reversing multidrug resistance in tumor cells, whereas the stimulation of Pgp expression or activity has implication for chemoprotective enhancement by herbal medicines. Certain natural flavonols (e.g., kaempferol, quercetin, and galangin) are potent stimulators of the Pgp-mediated efflux of 7,12-dimethylbenz(a)-anthracene (a carcinogen). The modulation of Pgp activity and expression by these herb constituents may result in altered absorption and bioavailability of drugs that are Pgp substrates. This is exemplified by increased oral bioavailability of phenytoin and rifampin by piperine and decreased bioavailability of indinavir, tacrolimus, cyclosporine, digoxin, and fexofenadine by coadministered St. John's wort. However, many of these drugs are also substrates of CYP3A4. Thus, the modulation of intestinal Pgp and CYP3A4 represents an important mechanism for many clinically important herb-drug interactions. Further studies are needed to explore the relative role of Pgp and CYP3A4 modulation by herbs and the mechanism for the interplay of these two important proteins in herb-drug interactions.
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PMID:Herbal modulation of P-glycoprotein. 1507 39

Silymarin consists of a family of flavonoids (silybin, isosilybin, silychristin, silydianin and taxifoline) commonly found in the dried fruit of the milk thistle plant Silybum marianum. Although silymarin's role as an antioxidant and hepatoprotective agent is well known, its role as an anticancer agent has begun to emerge. Extensive research within the last decade has shown that silymarin can suppress the proliferation of a variety of tumor cells (e.g., prostate, breast, ovary, colon, lung, bladder); this is accomplished through cell cycle arrest at the G1/S-phase, induction of cyclin-dependent kinase inhibitors (such as p15, p21 and p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-kappaB). Silymarin can also down-regulate gene products involved in the proliferation of tumor cells (cyclin D1, EGFR, COX-2, TGF-beta, IGF-IR), invasion (MMP-9), angiogenesis (VEGF) and metastasis (adhesion molecules). The antiinflammatory effects of silymarin are mediated through suppression of NF-kappaB-regulated gene products, including COX-2, LOX, inducible iNOS, TNF and IL-1. Numerous studies have indicated that silymarin is a chemopreventive agent in vivo against a variety of carcinogens/tumor promoters, including UV light, 7,12-dimethylbenz(a)anthracene (DMBA), phorbol 12-myristate 13-acetate (PMA) and others. Silymarin has also been shown to sensitize tumors to chemotherapeutic agents through down-regulation of the MDR protein and other mechanisms. It binds to both estrogen and androgen receptors, and down-regulates PSA. In addition to its chemopreventive effects, silymarin exhibits antitumor activity against human tumors (e.g., prostate and ovary) in rodents. Various clinical trials have indicated that silymarin is bioavailable and pharmacologically safe. Studies are now in progress to demonstrate the clinical efficacy of silymarin against various cancers.
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PMID:Anticancer potential of silymarin: from bench to bed side. 1720 Nov 69


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