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 (or P-gp1, ABCB1) expression in tumor cells is causative of multidrug resistance through the active efflux of drugs across the cell membrane. However, the over-expression of P-glycoprotein in some tumor cells has been associated with increased sensitivity, or "collateral sensitivity", of multidrug resistant cells to specific drugs, including the calcium channel blocker verapamil. We previously demonstrated that collateral sensitivity to verapamil correlates with the effect of this drug on P-gp1 ATPase, and is reversed by inhibitors of P-gp1 ATPase (e.g., PSC 833 and Ivermectin). In this report, we expand on our earlier study and demonstrate that P-gp1 expression in drug-resistant cells modulates collateral sensitivity. Using P-gp1-specific siRNA, P-gp1 expression in the multidrug resistant CH(R)C5 cells was significantly down-regulated beginning on day 2 post-transfection of siRNA. Furthermore, down-regulation of P-gp1 led to increased sensitivity of CH(R)C5 cells to paclitaxel and doxorubicin, but not to cis-platinum, due to inhibition of P-gp1 drug efflux pump. Down-regulation of P-gp1 expression completely reversed collateral sensitivity to verapamil. Moreover, known inhibitors of ETC, rotenone and antimycin A which cause an increase in reactive oxygen species, synergized with verapamil-induced collateral sensitivity leading to increased cell death as determined by MTT cell survival assay. Similarly, the addition of hydrogen peroxide also synergized with verapamil. Taken together, the results of this study demonstrate a direct link between P-gp1 expression and collateral sensitivity of drug-resistant cells, possibly due to an increase in reactive oxygen species.
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PMID:P-glycoprotein (ABCB1) modulates collateral sensitivity of a multidrug resistant cell line to verapamil. 1977 51

A synthetic amphiphilic block copolymer, Pluronic, is a potent chemosensitizer of multidrug resistant (MDR) cancers that has shown promise in clinical trials. It has unique activities in MDR cells, which include a decrease in ATP pools and inhibition of P-glycoprotein (Pgp) resulting in increased drug accumulation in cells. This work demonstrates that Pluronic rapidly (15min) translocates into MDR cells and co-localizes with the mitochondria. It inhibits complex I and complex IV of the mitochondria respiratory chain, decreases oxygen consumption and causes ATP depletion in MDR cells. These effects are selective and pronounced for MDR cells compared to non-MDR counterparts and demonstrated for both drug-selected and Pgp-transfected cell models. Furthermore, inhibition of Pgp functional activity also abolishes the effects of Pluronic on intracellular ATP levels in MDR cells suggesting that Pgp contributes to increased responsiveness of molecular "targets" of Pluronic in the mitochondria of MDR cells. The Pluronic-caused impairment of respiration in mitochondria of MDR cells is accompanied with a decrease in mitochondria membrane potential, production of ROS, and release of cytochrome c. Altogether these effects eventually enhance drug-induced apoptosis and contribute to potent chemosensitization of MDR tumors by Pluronic.
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PMID:Differential metabolic responses to pluronic in MDR and non-MDR cells: a novel pathway for chemosensitization of drug resistant cancers. 1981 37

Blood-brain barrier efflux transporters limit the brain penetration and efficacy of various central nervous system drugs. In several CNS diseases, therapy- or pathophysiology-associated transcriptional activation of efflux transporters further strengthens the barrier function. Targeting the regulatory pathways that drive efflux transporter expression in different diseases represents an intriguing approach for prevention of these events thereby promoting delivery to the brain and enhancing or restoring drug efficacy. In particular, the approach holds the promise to preserve basal transporter expression and activity, which is of specific relevance in view of the protective function of efflux transport. The elucidation of the signaling cascades involved in transporter regulation is a major presupposition for the development of preventive strategies. Orphan nuclear receptors as well as the Wnt/beta-catenin signaling pathway have been implicated in drug-induced changes in transporter expression. Targeting these xenobiotic sensors is therefore discussed as a means to optimize brain delivery and therapeutic outcome. Relevant progress has also been made with the identification of key signaling events that drive P-glycoprotein expression in response to pathophysiological mechanisms. In the epileptic brain, complex signaling events involving cyclooxygenase-2 activity trigger P-glycoprotein expression in response to glutamate release and activation of endothelial NMDA receptors. Moreover, reactive oxygen species and inflammatory cytokines have been identified as regulatory factors which might affect P-glycoprotein in several CNS diseases. Recent data substantiated several interesting targets in the respective signaling cascades thereby rendering a basis for the ongoing development of innovative approaches to optimize central nervous system drug brain penetration and efficacy.
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PMID:Targeting regulation of ABC efflux transporters in brain diseases: a novel therapeutic approach. 1989 2

In photodynamic therapy (PDT) a tumor-selective photosensitizer is administered and then activated by exposure to a light source of appropriate wavelength. Multidrug resistance (MDR) is largely caused by the drug efflux from the tumor cell by means of P-glycoprotein, resulting in reduced efficacy of the anticancer therapy. This study deals with photodynamic therapy with Photofrin (Ph) on colon cancer cell lines (doxorubicin-sensitive and -resistant). The cells were treated with 15 and 30 microg/mL Ph and then irradiated by a light dose of 3 or 6 J/cm(2) (632.8 nm). After irradiation the cells were incubated for 0, 3 or 18 h. Crucial factors of oxidative stress (thiobarbituric acid reactive substances [TBARS], protein damage, thiazolyl blue tetrazolium bromide [MTT] assay), changes in cytosolic superoxide dismutase (SOD1) activity after photodynamic reaction (PDR), and the intracellular accumulation of photosensitizers in the cells were examined. Moreover, the expressions of glutathione S-transferase (GST)-pi, a marker protein for photochemical toxicity, and secretory phospholipase A(2), a prognostic and diagnostic marker for colon cancers, were determined. After PDR, increases in SOD1 activity and the level of TBARS were observed in both cell lines. The level of protein-associated -SH groups decreased after PDR. Both cell lines demonstrated stronger GST-pi and PLA(2) expression after PDR, especially after 18 h of incubation. The increasing level of reactive oxygen species following the oxidation of sulfhydryl cell groups and lipid peroxidation influence the activity of many transporters and enzymes. The changes in SOD1 activity show that photodynamic action generates oxidative stress in treated cells. Our study presents that PDR caused oxidative alterations in both examined colon adenocarcinoma cell lines. However, the MDR cells reacted more slowly and all oxidative changes occurred in the delay.
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PMID:Oxidative alterations induced in vitro by the photodynamic reaction in doxorubicin-sensitive (LoVo) and -resistant (LoVoDX) colon adenocarcinoma cells. 2040 24

Drug resistance is a major challenge to the effective treatment of cancer. We have developed two nanoparticle formulations, cationic liposome-polycation-DNA (LPD) and anionic liposome-polycation-DNA (LPD-II), for systemic co-delivery of doxorubicin (Dox) and a therapeutic small interfering RNA (siRNA) to multiple drug resistance (MDR) tumors. In this study, we have provided four strategies to overcome drug resistance. First, we formed the LPD nanoparticles with a guanidinium-containing cationic lipid, i.e. N,N-distearyl-N-methyl-N-2-(N'-arginyl) aminoethyl ammonium chloride, which can induce reactive oxygen species, down-regulate MDR transporter expression, and increase Dox uptake. Second, to block angiogenesis and increase drug penetration, we have further formulated LPD nanoparticles to co-deliver vascular endothelial growth factor siRNA and Dox. An enhanced Dox uptake and a therapeutic effect were observed when combined with vascular endothelial growth factor siRNA in the nanoparticles. Third, to avoid P-glycoprotein-mediated drug efflux, we further designed another delivery vehicle, LPD-II, which showed much higher entrapment efficiency of Dox than LPD. Finally, we delivered a therapeutic siRNA to inhibit MDR transporter. We demonstrated the first evidence of c-Myc siRNA delivered by the LPD-II nanoparticles down-regulating MDR expression and increasing Dox uptake in vivo. Three daily intravenous injections of therapeutic siRNA and Dox (1.2 mg/kg) co-formulated in either LPD or LPD-II nanoparticles showed a significant improvement in tumor growth inhibition. This study highlights a potential clinical use for the multifunctional nanoparticles with an effective delivery property and a function to overcome drug resistance in cancer. The activity and the toxicity of LPD- and LPD-II-mediated therapy are compared.
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PMID:Multifunctional nanoparticles delivering small interfering RNA and doxorubicin overcome drug resistance in cancer. 2046 Mar 82

A novel approach to circumvent multidrug resistance is hybridization of natural products in dimers. We analyzed homodimers of two artesunic acid molecules and heterohybrids of artesunic acid and betulin in human CCRF-CEM and multidrug-resistant P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells. Multidrug-resistant cells were not cross-resistant to the novel compounds. Collateral sensitivity was observed for artesunic acid homodimer. Artesunic acid and artesunic acid homodimer induced G0/G1 cell cycle arrest, apoptosis, and formation of reactive oxygen species.
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PMID:Cytotoxicity of artesunic acid homo- and heterodimer molecules toward sensitive and multidrug-resistant CCRF-CEM leukemia cells. 2052 17

Anthracycline antibiotics have saved the lives of many cancer victims in the 50 plus years since their discovery. A major limitation of their use is the dose-limiting cardiotoxicity. Efforts focusing on understanding the biochemical basis for anthracycline cardiac effects have provided several strategies currently in clinical use: limit dose exposure, encapsulate anthracyclines in liposomes to reduce myocardial uptake, administer concurrently with the iron chelator dexrazoxane to reduce free iron-catalyzed reactive oxygen species formation; and modify anthracycline structure in an effort to reduce myocardial toxicity. Despite these efforts, anthracycline-induced heart failure continues to occur with consequences for both morbidity and mortality. Our inability to predict and prevent anthracycline cardiotoxicity is, in part, due to the fact that the molecular and cellular mechanisms remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes in vitro and small animals in vivo have demonstrated several forms of cardiac injury, and it remains unclear how these translate to the clinical setting. Given the clinical evidence that myocyte death occurs after anthracycline exposure in the form of elevations in serum troponin, myocyte cell death seems to be a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular "sarcopenia" characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. There is now evidence that erbB2 signaling in response to the ligand neuregulin regulates anthracycline uptake into cells via the multidrug-resistance protein. Therefore, up-regulation of cardiac neuregulin signaling may be one strategy to limit myocardial anthracycline injury. Moreover, assessing an individual's risk for anthracycline injury may be improved by having some measure of endogenous activity of this and other myocardial protective signals.
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PMID:Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection? 2072 97

In early studies, it was demonstrated that R-HZ08, S-HZ08 and the racemate had strong reverse efficacy of multidrug resistance in vitro and in vivo (Yan et al., 2008b). The effect was supposed to have direct interaction with multidrug resistance-associated protein (MRP1) in MCF-7/ADM and P-glycoprotein in K562/A02. According to our latest study, we found HZ08 could enhance chemotherapy induced apoptosis by synergistic action on reactive oxygen species generation, GSH depletion, mitochondrial membrane potential depolarization, cytochrome c release and caspase activation. Moreover, the potential selective effect of HZ08 on resistant cells suggested that HZ08 have specific targets for resistance reversal via apoptosis regulation. Therefore, we traced individual influence of HZ08, not only on apoptosis pathway per se but also on apoptosis related intracellular regulation systems. Then we found HZ08 could increase cells in G(0)/G(1) phase and regulate apoptosis related proteins (Bcl-2, Bax) as well as upstream functional molecules (c-Myc and c-Fos), which are usually abnormal in malignancy and responsible for multidrug resistance in MCF-7/ADM. Thereby, chemotherapy induced apoptosis was promoted. R-HZ08 showed better effect than S-HZ08 or the racemate did in most of targets above. Furthermore, HZ08 did not change the concentration of intracellular Ca(2+) which means it would not have side effect as verapamil does. Considering multidrug resistance is multifactorial, HZ08, especially R-HZ08, which could sensitize apoptosis by multiple improvements of upstream malignant characters, will be a promising drug to enhance the effect of chemotherapy in the treatment of multidrug resistant tumor.
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PMID:HZ08, a great regulator to reverse multidrug resistance via cycle arrest and apoptosis sensitization in MCF-7/ADM. 2081 13

Multidrug resistance (MDR) mediated by the over expression of drug efflux protein P-glycoprotein (P-gp) is one of the major impediments to successful treatment of cancer. P-gp acts as an energy-dependent drug efflux pump and reduces the intracellular concentration of structurally unrelated drugs inside the cells. Therefore, there is an urgent need for development of new molecules that are less toxic to normal cell and preferentially effective against drug resistant malignant cells. In this preclinical study we report the apoptotic potential of copper N-(2-hydroxyacetophenone) glycinate (CuNG) on doxorubicin resistant T lymphoblastic leukaemia cells (CEM/ADR5000). To evaluate the cytotoxic effect of CuNG, we used different normal cell lines (NIH 3T3, Chang liver and human PBMC) and cancerous cell lines (CEM/ADR5000, parental sensitive CCRF-CEM, SiHa and 3LL) and conclude that CuNG preferentially kills cancerous cells, especially both leukemic cell types irrespective of their MDR status, while leaving normal cell totally unaffected. Moreover, CuNG involves reactive oxygen species (ROS) for induction of apoptosis in CEM/ADR5000 cells through the intrinsic apoptotic pathway. This is substantiated by our observation that antioxidant N-acetyle-cysteine (NAC) and PEG catalase could completely block ROS generation and, subsequently, abrogates CuNG induced apoptosis. On the other hand, uncomplexed ligand N-(2-hydroxyacetophenone) glycinate (NG) fails to generate a significant amount of ROS and concomitant induction of apoptosis in CEM/ADR5000 cells. Therefore, CuNG induces drug resistant leukemia cells to undergo apoptosis and proves to be a molecule having therapeutic potential to overcome MDR in cancer.
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PMID:Redox active copper chelate overcomes multidrug resistance in T-lymphoblastic leukemia cell by triggering apoptosis. 2140 5

We have developed a drug-resistant cell line (RIF/Ptr1) (R) from the murine radiation-induced fibrosarcoma (RIF-1) also designated Pts or (S). This subline has been characterized previously by an increased resistance to cisplatin (cis-diamminedichloroplatinum(II) or CDDP), lowered intracellular CDDP concentrations, and elevated intracellular glutathione (GSH) levels (1.4-2.5-fold) but unaltered formation of CDDP-DNA interstrand cross-links. In this work, we have shown that RIF/Ptr1 cells were also resistant to carmustine (BCNU) and X-irradiation. Neither cell line had P-glycoprotein 170. The intrastrand CDDP-DNA adduct level was proportional to the concentration of intracellular CDDP. The oxygen consumption, ATP level, and glycolysis were similar in both cell lines. The cisplatin influx and efflux showed that the RIF/Ptr1 cells had lower drug influx and higher drug efflux compared to RIF-1. We conclude that the major difference between the cisplatin sensitive and cisplatin-resistant cells in this model is the regulation of cisplatin transport probably at the cell membrane level suggesting that a membrane active transport system other than P-glycoprotein 170 is involved. Whether glutathione is linked to the putative membrane transporter needs further investigation.
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PMID:Partial characterization of a Cisplatin-resistant subline of murine rif-1 tumor-cells. 2155 86


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