Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

Xia, Cindy Q.; Smith, Peter G.

doi:10.1124/mol.112.079129

Cited by 81 publications

(57 citation statements)

References 184 publications

(170 reference statements)

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“…Expression of the membrane-proximal KXGFFKR motif leads to enhanced drug efflux. A well-known cellular physiological adaptation contributing to chemoresistance in leukemia is enhanced expression and activity of drug efflux transporters (36). A recent CAM-DR study reported that integrin-␤1 mediated adhesion of Jurkat cells stimulated the expression of the p-glycoprotein transporter MRP1 and decreased intracellular accumulation of doxorubicin (37).…”

Section: Resultsmentioning

confidence: 99%

“…We noted with interest in previous studies that T cell adhesion on various substrates promoted elevations of intracellular Ca 2ϩ (35) and that Ca 2ϩ channel-blocking agents can restore chemosensitivity (36). This led us to explore the possibility that integrin-mediated chemoresistance is coupled to regulation of Ca 2ϩ flux in CAM-DR. First, we measured intracellular Ca 2ϩ levels by using the cellpermeant fluorescent Ca 2ϩ indicator Fluo-4-AM in the various JB4 cells under nonadherent conditions.…”

Section: Resultsmentioning

confidence: 99%

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The Membrane-Proximal KXGFFKR Motif of α-Integrin Mediates Chemoresistance

Liu¹,

Leclair

Yap

et al. 2013

Molecular and Cellular Biology

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Cell adhesion-mediated drug resistance contributes to minimal residual disease and relapse in hematological malignancies. Here, we show that adhesion of Jurkat T-acute lymphoblastic leukemia cells to substrates engaging ␣4␤1-integrin or ␣5␤1-integrin promotes chemoresistance to doxorubicin-induced apoptosis. Reconstituted expression of ␣4␦, a truncated ␣4-integrin with KXGFFKR as the cytoplasmic motif, in ␣4-deficient cells promoted chemoresistance to doxorubicin in a manner independent of ␣4-mediated adhesion. The adhesion-independent chemoresistance did not require ␤1-integrin as the heterodimeric pair, since expression of Tac␦, a monomeric nonintegrin transmembrane protein fused to the juxtamembrane KXGFFKR, was sufficient to reproduce the phenomenon. The requirement for integrin-mediated adhesion in stimulation of Akt phosphorylation and activation was bypassed for cells expressing ␣4␦ and Tac␦. Cells expressing ␣4␦ and Tac␦ exhibited a high influx of extracellular Ca 2؉ , and inhibition of Ca 2؉ channels with verapamil attenuated the adhesion-independent chemoresistance. Tac␦ cells also exhibited greater rates of drug efflux. ␣4␦ and Tac␦ interacted with the Ca 2؉ -binding protein calreticulin, in a manner dependent on the KXGFFKR motif. Adhesion-mediated engagement of ␣4-integrins promoted an increased calreticulin-␣4 association and greater influx of extracellular Ca 2؉ than in nonadherent cells. The ␣-integrin KXGFFKR motif is involved in adhesion-mediated control of chemoresistance in T cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The Membrane-Proximal KXGFFKR Motif of α-Integrin Mediates Chemoresistance

Liu¹,

Leclair

Yap

et al. 2013

Molecular and Cellular Biology

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“…ABCB1 encodes a transmembrane protein with 1280 amino acids, with 40% sequence identity between its NH2-and COOH-terminal halves, which are connected by an 80-amino-acid linker region (Bourne et al, 1986). The importance of P-gp has been demonstrated in numerous in vitro, in vivo, and clinical studies (Shukla et al, 2011;Xia and Smith, 2012). ABCG2, also known as breast cancer resistance protein, is another major human multidrug transporter (Robey et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Using the BacMam Baculovirus System to Study Expression and Function of Recombinant Efflux Drug Transporters in Polarized Epithelial Cell Monolayers

Fung

Kapoor

Pixley

et al. 2015

Drug Metabolism and Disposition

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The ATP-binding cassette (ABC) transporter superfamily includes several membrane-bound proteins that are critical to drug pharmacokinetics and disposition. Pharmacologic evaluation of these proteins in vitro remains a challenge. In this study, human ABC transporters were expressed in polarized epithelial cell monolayers transduced using the BacMam baculovirus gene transfer system. The purpose of the study was to evaluate the efficacy of BacMam baculovirus to transduce cells grown in monolayers. In a porcine kidney cell line, LLC-PK1 cells, baculoviral transduction is successful only via the apical side of a polarized monolayer. We observed that recombinant ABC transporters were expressed on the cell surface with post-translational modification. Furthermore, sodium butyrate played a critical role in recombinant protein expression, and preincubation in the presence of tunicamycin or thapsigargin enhanced protein expression. Cells overexpressing human P-glycoprotein (P-gp) showed vectorial basolateral-to-apical transport of [ 3 H]-paclitaxel, which could be reversed by the inhibitor tariquidar. Similarly, coexpression of human P-gp and ABCG2 in LLC-PK1 cells resulted in higher transport of mitoxantrone, which is a substrate for both transporters, than in either P-gp-or ABCG2-expressing cells alone. Taken together, our results indicate that a high level of expression of efflux transporters in a polarized cell monolayer is technically feasible with the BacMam baculovirus system

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“…In hematological malignancies, P-gp mRNA expression and protein function are increased after chemotherapy treatment. Expression of P-gp in myeloid blasts is correlated with treatment failure and shorter survival in adult acute myeloid leukemia (AML) patients [34,35] . However, childhood acute lymphoblastic leukemia (ALL) results have shown contradictory results, some found no association between high P-gp expression and prognosis [36,37] , while other groups showed prognostic impact for P-gp in ALL [38,39] .…”

Section: Introductionmentioning

confidence: 99%

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Jaramillo¹,

Saig²,

Cloos³

et al. 2018

CDR

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P-glycoprotein (ABCB1), multidrug resistance protein-1 (ABCC1) and breast cancer resistance protein (ABCG2) belong to the ATP-binding cassette (ABC) superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites. Beyond this, these transporters determine the toxicity profile of many drugs, and confer multidrug resistance (MDR) in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR, but until now no approved inhibitor of these transporters is available in the clinic. In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

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Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

Cited by 81 publications

References 184 publications

The Membrane-Proximal KXGFFKR Motif of α-Integrin Mediates Chemoresistance

The Membrane-Proximal KXGFFKR Motif of α-Integrin Mediates Chemoresistance

Using the BacMam Baculovirus System to Study Expression and Function of Recombinant Efflux Drug Transporters in Polarized Epithelial Cell Monolayers

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

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