P-glycoprotein: The intermediate end point of drug response to induction chemotherapy in locally advanced breast cancer

Chung, Hyun Cheol; Rha, Sun Young; Kim, Joo Hang; Roh, Jae Kyung; Min, Jin Sik; Lee, Kyung Sik; Kim, Byung Soo; Lee, Kyi Beom

doi:10.1023/a:1005739525196

Cited by 38 publications

(31 citation statements)

References 25 publications

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“…Moreover, we observed secreted P-gp in brain endothelial cell culture supernatants, suggesting P-gp is cleaved and released into the extracellular environment. Consistent with this notion, since molecules enter the CNS by transcellular and/or paracellular routes and the transcellular pathway is regulated by efflux transporters, such as P-gp, we wished to determine whether AR signaling also exerts regulatory effects on the transcellular pathway of the BBB mediated by P-gp (5,11,17). Not surprisingly, many drugs are expelled by P-gp even before entering the brain and therefore are dropped from the drug pipeline in the course of their development (15).…”

Section: Discussionmentioning

confidence: 98%

“…Its broad substrate spectrum allows it to expel major classes of drugs (26,65). Moreover, P-gp expression or upregulation in various cancers and cell types poses a poor prognosis for cancers and cancer treatment (17). Therefore, our data showing that signaling via the A2A AR alters P-gp function have very broad appeal beyond the CNS.…”

Section: Subcellular Localization Analysis Of P-gp In Brain Endothelimentioning

confidence: 91%

“…It was first observed and described in drug-resistant cancer cells that highly expressed it. In breast cancer cells, P-gp prevents effective chemotherapeutic treatment by blocking chemotherapeutic drug uptake (17)(18)(19). Later studies showed that P-gp is also highly expressed on capillaries of the liver, sex organs, and the brain and is involved in expulsion of xenobiotics from the CNS (20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

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A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

Kim¹,

Bynoe²

2016

Journal of Clinical Investigation

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The blood-brain barrier (BBB) protects the brain from toxic substances within the peripheral circulation. It maintains brain homeostasis and is a hurdle for drug delivery to the CNS to treat neurodegenerative diseases, including Alzheimer's disease and brain tumors. The drug efflux transporter P-glycoprotein (P-gp) is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Here, we show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a timedependent and reversible manner. We demonstrate that downmodulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models. Lexiscan also potently downregulated the expression of BCRP1, an efflux transporter that is highly expressed in the CNS vasculature and other tissues. Finally, we determined that multiple pathways, including MMP9 cleavage and ubiquitinylation, mediated P-gp downmodulation. Based on these data, we propose that A2A AR activation on BBB endothelial cells offers a therapeutic window that can be fine-tuned for drug delivery to the brain and has potential as a CNS drug-delivery technology.

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Section: Discussionmentioning

confidence: 98%

Section: Subcellular Localization Analysis Of P-gp In Brain Endothelimentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

Kim¹,

Bynoe²

2016

Journal of Clinical Investigation

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“…P-gp is an ATP-binding-cassette transporter that is ubiquitously expressed, and often has high concentrations on plasma membrane of cancer cells, where it causes multidrug resistance by pumping lipophilic drugs out of the cell. The expression of P-gp influenced the efficacy of postoperative chemotherapy [17][18][19][20][21][22][23][24] . In our study, P-gp expression rate was 62.5 % which was similar to the result of another report on hepatocellular carcinoma [25] .…”

Section: Discussionmentioning

confidence: 99%

Correlation of P-glycoprotein expression with poor vascularization in human gallbladder carcinomas

Tian

Li-li²,

Guo³

et al. 2003

WJG

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AIM:To investigate the relationship between the expression of P-glycoprotein (P-gp) and the degree of vascularization in gallbladder carcinomas.METHODS: P-gp was stained with streptavidin-peroxidase complex immunohistochemical method in routine paraffinembedded sections of gallbladder carcinomas. Microvessel counts (MVC) were determined using factor-VIII-related antigens. RESULTS:The average MVC in 32 cases of gallbladder carcinomas was (34±10)/HP. The value of MVC was closely correlated with Nevin staging and tumor differentiation (P<0.01 and P<0.05). The total expression rate of P-gp was 62.5 %. The P-gp expression rate in cases of Nevin staging S1-S3 (78.6 %) was higher than that of S4-S5 (50.0 %) with no statistical significance. The P-gp expression rate was not correlated with tumor differentiation or pathologic types. The value of MVC in P-gp (+) cases was markedly lower than that in P-gp (-) cases (P<0.01). The positive rate of P-gp was significantly higher in cases of smaller MVC than those of bigger MVC (P<0.05).CONCLUSION: MVC may be used as one of the important parameters to reflect the biological behaviors of gallbladder carcinomas. As a major cause of drug resistance, the overexpression of P-gp is closely correlated with the poor vascularization in gallbladder carcinomas.Tian Y, Zhu LL, Guo RX, Fan CF. Correlation of P-glycoprotein expression with poor vascularization in human gallbladder carcinomas.

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“…This may be because P-gp expression is inducible by chemotherapy, and treatment-induced up-regulation of this molecule may be more important in determining resistance than baseline expression. [3][4][5] Technetium-99m-sestamibi ( 99m Tc-sestamibi) is also a P-gp substrate and provides a method with which assess the functional activity of this drug transporter in vivo. Tumors with high P-gp expression show faster clearance and less intracellular accumulation of this radiotracer.…”

mentioning

confidence: 99%

Phase II study of tariquidar, a selective P‐glycoprotein inhibitor, in patients with chemotherapy‐resistant, advanced breast carcinoma

Pusztai

Wagner

Ibrahim

et al. 2005

Cancer

257

137

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BACKGROUNDThe primary objective of this study was to determine whether addition of the selective P‐glycoprotein (P‐gp) inhibitor tariquidar (XR9576) to chemotherapy could induce an objective tumor response in patients who previously were resistant to the same agents. The secondary objectives were to evaluate P‐gp expression by immunohistochemistry (IHC), to determine functional activity of the P‐gp transporter before and after administration of tariquidar with serial technetium‐99m (99mTc)‐sestamibi scans, and to correlate those parameters with clinical response.METHODSSeventeen women with Stage III–IV breast carcinoma were included in the study who progressed (n = 13 women) or had stable disease (n = 4 women) on doxorubicin‐containing or taxane‐containing chemotherapy regimens. During the study, the same chemotherapy was continued without dose modifications, but tariquidar (150 mg intravenously) was added to the treatment regimen.RESULTSThirty‐six percent of patients had P‐gp‐positive tumors by IHC, and 5 patients (29%) experienced increases ≥ 10% in sestamibi uptake (median increase, 40%; range, 10–63%) after the administration of tariquidar. There was one partial response in a patient who had the greatest increase in sestamibi uptake and who also showed inducible P‐gp expression. There was one patient who experienced severe doxorubicin/docetaxel‐related toxicity after tariquidar was added to her chemotherapy regimen.CONCLUSIONSTariquidar showed limited clinical activity to restore sensitivity to anthracycline or taxane chemotherapy. Functional imaging of the tumor with 99mTc‐sestamibi scans before and after administration of multidrug‐resistance inhibitor may be useful to identify the small subset of patients who could benefit from multidrug‐resistance modulation in future trials. Cancer 2005. © 2005 American Cancer Society.

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P-glycoprotein: The intermediate end point of drug response to induction chemotherapy in locally advanced breast cancer

Cited by 38 publications

References 25 publications

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

Correlation of P-glycoprotein expression with poor vascularization in human gallbladder carcinomas

Phase II study of tariquidar, a selective P‐glycoprotein inhibitor, in patients with chemotherapy‐resistant, advanced breast carcinoma

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