Modulation of the typical multidrug resistance phenotype by targeting the MED-1 region of human MDR1 promoter

Marthinet, Eric; Divita, Gilles; Bernaud, Janine; Rigal, D; Baggetto, Loïc

doi:10.1038/sj.gt.3301231

Cited by 38 publications

(22 citation statements)

References 40 publications

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“…These approaches include monoclonal antibodies such as MRK16 24 or immunotoxins against Pgp, 25 antisense oligonucleotides for the specific inhibition of P-gp gene expression, 17 and the transcriptional decoy strategies. 26 The present study was designed to determine if siRNA against MDR1 gene can effectively inhibit expression of MDR1 gene product, P-gp. We first designed three different siRNAs targeting MDR1 gene and tested their effectiveness in silencing MDR1 mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA (siRNA) in leukemia cells

et al. 2004

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The multidrug resistance (MDR) mediated by P-glycoprotein (P-gp), the MDR1 gene product, is one of the major obstacles in leukemia treatment. The present study was designed to explore a MDR1-targeted small interfering RNA (si-MDR1) approach for reversal of P-gp-mediated MDR in the MDR human leukemia cell line k562/A02. It was found that si-MDR1 significantly inhibited MDR1 expression at both mRNA and protein levels. Depletion of MDR1 by si-MDR1 correlated with the increased sensitivity of the cells to cytotoxic agents and with the enhanced intracellular retention of daunorubicin (DNR). One base-pair mutated control (si-MDR1-Mut) lost the effect of si-MDR1 on both the degradation of mdr1 mRNA and the reduction of P-gp expression. These findings indicate that siRNA specifically and efficiently interferes with the expression of mdr1 and could be used as a molecularly defined therapeutic approach for MDR in the treatment of leukemia.

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Section: Discussionmentioning

confidence: 99%

Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA (siRNA) in leukemia cells

et al. 2004

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“…As mentioned above, a multiple start site element is present in the ABCB1 promoter, which was found to be functional in the activation of the gene in drug-resistant cell lines (228). In a recent report, this site (invMED1) was precisely localized between Ϫ105 and Ϫ100 bp, and the LRP130 protein was identified as a component of the nuclear factor that binds to the invMED1 site (199).…”

Section: Transcriptional Regulationmentioning

confidence: 99%

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Sarkadi¹,

Homolya²,

Szakács³

et al. 2006

Physiological Reviews

645

532

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In this review we give an overview of the physiological functions of a group of ATP binding cassette (ABC) transporter proteins, which were discovered, and still referred to, as multidrug resistance (MDR) transporters. Although they indeed play an important role in cancer drug resistance, their major physiological function is to provide general protection against hydrophobic xenobiotics. With a highly conserved structure, membrane topology, and mechanism of action, these essential transporters are preserved throughout all living systems, from bacteria to human. We describe the general structural and mechanistic features of the human MDR-ABC transporters and introduce some of the basic methods that can be applied for the analysis of their expression, function, regulation, and modulation. We treat in detail the biochemistry, cell biology, and physiology of the ABCB1 (MDR1/P-glycoprotein) and the ABCG2 (MXR/BCRP) proteins and describe emerging information related to additional ABCB- and ABCG-type transporters with a potential role in drug and xenobiotic resistance. Throughout this review we demonstrate and emphasize the general network characteristics of the MDR-ABC transporters, functioning at the cellular and physiological tissue barriers. In addition, we suggest that multidrug transporters are essential parts of an innate defense system, the “chemoimmunity” network, which has a number of features reminiscent of classical immunology.

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“…Indeed, MDR1 transcription has been targeted with Ecteinascidin 743 in pre-clinical studies (5) and more recently by modulation of the nuclear receptor SXR (6). Strategies involving antisense and transcriptional decoy (7) and the use of anti-MDR1 mRNA hammerhead ribozymes have also been suggested (8).…”

Section: Mdrmentioning

confidence: 99%

P-glycoprotein (MDR1) Expression in Leukemic Cells Is Regulated at Two Distinct Steps, mRNA Stabilization and Translational Initiation

Yagüe

Armesilla

Harrison

et al. 2003

Journal of Biological Chemistry

123

132

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Multidrug resistance in acute myeloid leukemia is often conferred by overexpression of P-glycoprotein, encoded by the MDR1 gene. We have characterized the key regulatory steps in the development of multidrug resistance in K562 myelogenous leukemic cells. Unexpectedly, up-regulation of MDR1 levels was not due to transcriptional activation but was achieved at two distinct posttranscriptional steps, mRNA turnover and translational regulation. The short-lived (half-life 1 h) MDR1 mRNA of naïve cells (not exposed to drugs) was stabilized (halflife greater than 10 h) following short-term drug exposure. However, this stabilized mRNA was not associated with translating polyribosomes and did not direct Pglycoprotein synthesis. Selection for drug resistance, by long-term exposure to drug, led to resistant lines in which the translational block was overcome such that the stabilized mRNA was translated and P-glycoprotein expressed. The absence of a correlation between steadystate MDR1 mRNA and P-glycoprotein levels was not restricted to K562 cells but was found in other lymphoid cell lines. These findings have implications for the avoidance or reversal of multidrug resistance in the clinic. MDR1 is the most common impediment to successful chemotherapy for a variety of cancers (1). The most frequent form of drug resistance in relapsed acute leukemia is overexpression of P-glycoprotein (2, 3). P-glycoprotein is a member of the ATPbinding cassette superfamily of active transporters and functions as an energy-dependent efflux pump that reduces the intracellular concentration of cytotoxic compounds and, hence, their toxicity. P-glycoprotein has a broad substrate specificity and can confer resistance to a wide range of different cytotoxic compounds (4).Most pre-clinical and clinical efforts to overcome MDR aim to modulate P-glycoprotein activity. However, clinical trials of compounds that inhibit P-glycoprotein activity have had limited success and led to adverse pharmacokinetic side effects (1). It may, therefore, be more appropriate to target MDR1 expression. Indeed, MDR1 transcription has been targeted with Ecteinascidin 743 in pre-clinical studies (5) and more recently by modulation of the nuclear receptor SXR (6). Strategies involving antisense and transcriptional decoy (7) and the use of anti-MDR1 mRNA hammerhead ribozymes have also been suggested (8).Stresses such as short-term exposure to cytotoxic drugs results in the up-regulation of MDR1 mRNA levels in many cell lines (9 -13) and in human metastatic sarcomas in vivo (14). This is frequently due to transcriptional activation of the MDR1 gene and has been reported in many cell lines after different physical and chemical stimulations and in cells selected for resistance to a variety of cytotoxic drugs (5,9,10,15,16). In cell lines selected for drug resistance, increased MDR1 gene expression is also the result of amplification of the MDR1 locus and the appearance of self-replicating episomes (4). Gene rearrangements that constitutively activate MDR1 transcription have also...

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Modulation of the typical multidrug resistance phenotype by targeting the MED-1 region of human MDR1 promoter

Cited by 38 publications

References 40 publications

Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA (siRNA) in leukemia cells

Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA (siRNA) in leukemia cells

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

P-glycoprotein (MDR1) Expression in Leukemic Cells Is Regulated at Two Distinct Steps, mRNA Stabilization and Translational Initiation

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