A primer on the mechanics of P-glycoprotein the multidrug transporter

Hennessy, Martina; Spiers, Paul

doi:10.1016/j.phrs.2006.10.007

Cited by 180 publications

(130 citation statements)

References 183 publications

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“…Also, tumorsuppressor protein p53 has been both positively or negatively implicated in regulating MDR1 transcription. 1 The finding that P-gp activity was downregulated by perifosine at 6 h (that is, a time point where P-gp protein expression levels were not affected by the drug) is puzzling. However, it is established that P-gp exists in lipid rafts, 36 where it displays a more active state than when localized outside rafts.…”

Section: Discussionmentioning

confidence: 99%

“…1 MDR is a complex phenomenon, often associated with overexpression of the 170-kDa Pglycoprotein (P-gp) on the plasma membrane of tumor cells. P-gp is the product of the ABCB1 (MDR1) gene and belongs to the superfamily of ATP-binding cassette transporters, which actively efflux across the membranes a wide range of structurally diverse compounds used to treat cancer, thus reducing their intracellular bioavailability and toxicity.…”

Section: Introductionmentioning

confidence: 99%

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The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism

et al. 2008

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A significant impediment to the success of cancer chemotherapy is the occurrence of multidrug resistance, which, in many cases, is attributable to overexpression of membrane transport proteins, such as the 170-kDa P-glycoprotein (P-gp). Also, upregulation of the phosphatidylinositol 3-kinase (PI3K)/Aktsignaling pathway is known to play an important role in drug resistance, and has been implicated in the aggressiveness of a number of different cancers, including T-acute lymphoblastic leukemia (T-ALL). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine (a synthetic alkylphospholipid), on human T-ALL CEM cells (CEM-R), characterized by both overexpression of P-gp and constitutive upregulation of the PI3K/Akt network. Perifosine treatment induced death by apoptosis in CEM-R cells. Apoptosis was characterized by caspase activation, Bid cleavage and cytochrome c release from mitochondria. The proapoptotic effect of perifosine was in part dependent on the Fas/FasL interactions and c-Jun NH 2 -terminal kinase (JNK) activation, as well as on the integrity of lipid rafts. Perifosine downregulated the expression of P-gp mRNA and protein and this effect required JNK activity. Our findings indicate that perifosine is a promising therapeutic agent for treatment of T-ALL cases characterized by both upregulation of the PI3K/Akt survival pathway and overexpression of P-gp.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism

et al. 2008

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“…This response element binds a pregnane xenobiotic receptor/retinoid xenobiotic receptor a heterodimer (PXR/RXRa) leading to the activation of MDR1 transcription in response to a number of xenobiotic inducers. 24) Bile acid-activated farsenoid X receptor (FXR) forms a heterodimer with retinoid X receptor (RXR) and activates BSEP promoter activity upon binding to a specific bile acid response cis-element. 25) We previously reported that MTX treatment downregulated the expression level of PXR mRNA, but not FXR mRNA.…”

Section: Fig 1 Effect Of Mtx Treatment On Expression Levels Of Gapdmentioning

confidence: 99%

Effect of Methotrexate Treatment on Expression Levels of Organic Anion Transporter Polypeptide 2, P-Glycoprotein and Bile Salt Export Pump in Rats

Shibayama

Takeda

Yamada

2009

Biological & Pharmaceutical Bulletin

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High-dose methotrexate (HDMTX) chemotherapy with leucovorin (LV) rescue has been used as a therapeutic strategy in oncology since the 1970s. Adverse reactions following extension of methotrexate (MTX) elimination are a crucial problem in HDMTX chemotherapy. MTX is a substrate for drug transporters, which are multidrug resistance protein 2 (Mrp2), organic anion transporter polypeptide 2 (Oatp2) and other transporters. We previously reported that MTX treatment downregulated the expression level of Mrp2 in rats. Here we examined the effect of MTX treatment on the expression of Oatp2, P-glycoprotein (P-gp) and bile salt export pump (Bsep) in rats. MTX was single-injected intraperitoneally at a dose of 150 mg/kg, and Western blot analysis was performed. The levels of Oatp2, P-gp and Bsep in the liver on day 4 after treatment were downregulated to 36.3؎6.9%, 51.5؎5.2% and 61.8؎5.5% (mean؎S.E.M.) of controls, respectively. Expression levels of P-gp in the kidney and ileum were also downregulated to 38.5؎1.6% and 16.2؎1.6% of controls, respectively. These effects of MTX were partially recovered by LV, which rescues normal cells from MTX toxicity. In conclusion, the result indicates that MTX treatment downregulates expression levels of Oatp2, P-gp and Bsep.

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“…One of the downregulated proteins was found to be the nuclease-sensitive element-binding protein 1 (YB-1), a transcriptional factor that activates the expression of the multidrug resistance 1 protein (MDR1) in response to genotoxic stress (33). MDR1 pumps out a myriad of cytotoxic compounds, including paclitaxel; therefore, a putative decrease in MDR1 expression via YB-1 may explain the increased sensitivity of tumor cells to paclitaxel (34). Furthermore, YB-1 participates in the nucleotide excision repair pathway and plays a role in cisplatin-DNA adduct reparation (35); therefore, its downregulation may also account for the observed additive pattern in the combination of CIGB-300 plus cisplatin.…”

Section: Discussionmentioning

confidence: 99%

Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

Perera

Toro

Gorovaya

et al. 2014

Molecular and Clinical Oncology

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Abstract. CIGB-300 is a novel clinical-stage synthetic peptide that impairs the casein kinase 2 (CK2)-mediated phosphorylation of B23/nucleophosmin in different experimental settings and cancer models. As a single agent, CIGB-300 induces apoptosis in vitro and in vivo and modulates an array of proteins that are mainly involved in drug resistance, cell proliferation and apoptosis, as determined by proteomic analysis. However, the clinical oncology practice and cumulative knowledge on tumor biology suggest that drug combinations are more likely to cope with tumor complexity compared to single agents. In this study, we investigated the antiproliferative effect of CIGB-300 when combined with different anticancer drugs, such as cisplatin (alkylating), paclitaxel (antimitotic), doxorubicin (antitopoisomerase II) or 5-fluorouracil (DNA/RNA antimetabolite) in cell lines derived from lung and cervical cancer. Of note, using a Latin square design and subsequent analysis by CalcuSyn software, we observed that paclitaxel and cisplatin exhibited the best synergistic/additive profile when combined with CIGB-300, according to the combination and dose reduction indices. Such therapeutically favorable profiles may be explained by a direct cytotoxic effect and also by the observed cell cycle impairment following incubation of tumor cells with selected drug combinations. Importantly, on in vivo dose-finding schedules in human cervical tumors xenografted in nude mice, we observed that concomitant administration of CIGB-300 and cisplatin increased mice survival compared to single-agent treatment. Collectively, these findings provide a rationale for combining the anti-CK2 CIGB-300 peptide with currently available anticancer agents in the clinical setting and indicate platins and taxanes as compounds with major perspectives.

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A primer on the mechanics of P-glycoprotein the multidrug transporter

Cited by 180 publications

References 183 publications

The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism

The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism

Effect of Methotrexate Treatment on Expression Levels of Organic Anion Transporter Polypeptide 2, P-Glycoprotein and Bile Salt Export Pump in Rats

Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

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