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PubMed2006

MDR-1, but not MDR-3 gene expression, is associated with unmutated IgVH genes and poor prognosis chromosomal aberrations in chronic lymphocytic leukemia.

Two P-glycoprotein (P-gp) genes, MDR-1 (ABCB1) and MDR-3 (ABCB4), have been identified in humans. This study was designed to investigate whether associations exist between expression of MDR-1 and MDR-3 P-gp and other markers of poor prognosis and/or prior exposure to therapeutic agents in chronic lymphocytic leukemia (CLL). IgVH mutational status, gene usage, CD38 positivity, FISH analysis and clinical information were available on all patients. Twenty-one of 101 patients tested showed MDR-3 P-gp positivity. Associations with markers of poor prognosis or prior chemotherapy did not reach statistical significance, but MDR-3 P-gp positive patients had significantly shorter survivals than MDR-3 P-gp negative patients. MDR-1 P-gp expression (18/25) showed a strong association with unmutated IgVH genes and adverse prognosis cytogenetics (p = 0.015, p = 0.014, respectively), but was independent of prior exposure to chemotherapeutic agents. These results suggest a role for MDR-1 and MDR-3 in chemoresistant disease. This study highlights the value of determining MDR phenotype in CLL patients prior to treatment, to allow the design of novel drug regimens containing agents that reverse MDR function.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1990

Use of the polymerase chain reaction in the quantitation of mdr-1 gene expression.

The ability of the polymerase chain reaction (PCR) to quantitate expression of mRNA was examined in the present study. The model chosen was expression of the multidrug resistance gene mdr-1/Pgp in two colon carcinoma cell lines which express mdr-1/Pgp at levels comparable to those found in many clinical samples. PCR was utilized to evaluate differences in mdr-1/Pgp expression in the two cell lines after modulation by sodium butyrate. Thus, comparisons were made across a range of mdr-1/Pgp expression as well as comparisons of small differences. The PCR was found to be both sensitive and quantitative. Accurate quantitation requires demonstration of an exponential range which varies among samples. The exponential range can be determined by carrying out the PCR for a fixed number of cycles on serial dilutions of the RNA reverse transcription product, or by performing the reaction with a varying number of cycles on a fixed quantity of cDNA. By quantitation of the difference in PCR product derived from a given amount of RNA from the sodium butyrate treated and untreated cells, the difference in mRNA expression between samples can be determined. Normalization of the results can be achieved by independent amplification of a control gene, such as beta 2-microglobulin, when the latter is also evaluated in the exponential range. Simultaneous amplification of the control and target genes results in lower levels of PCR products due to competition, which varies from sample to sample. The PCR is thus a labor-intensive but sensitive method of quantitating gene expression in small samples of RNA.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Tax of the human T-lymphotropic virus type I transactivates promoter of the MDR-1 gene.

The mdr-1 gene has been shown to confer resistance to chemotherapy of multiple drugs which share no obvious structural similarities. We and others have previously reported that some virus-associated malignant cells express high levels of MDR-1 (1,2), probably regulated by some viral proteins. In this study we have examined the role of Tax, the key protein of HTLV-1. An excellent correlation was found between the existence of HTLV-1 and the expression of MDR-1 among seven human T-cell lines. In the second part of the study, a 1. 76-kb DNA fragment representing the upstream regulatory elements of human mdr-1 gene was cloned into the CAT reporter plasmid. When the Tax expression plasmid was co-transfected with the MDR-1 reporter plasmid, a significant induction of CAT activity was observed. We conclude that Tax protein may up-regulate the expression of the mdr-1 gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Multidrug resistance: molecular and clinical aspects.

Clinical drug resistance, a common and compromising side-effect during anticancer chemotherapy, is an acquired cellular resistance simultaneously to several cytotoxic drugs. Expression of the multidrug resistance gene (mdr) is one of the most-studied potential underlying mechanisms. The human mdr gene family encompasses two homologous members, the first of which, called the mdr1 gene, is the best-characterized so far. The human mdr1 gene has been shown to encode a membrane P-170 glycoprotein that, on the basis of its structure, is considered to act as a drug-efflux pump excreting various drugs from cells. The human mdr1 gene is thus a major regulated gene playing an important role in the molecular mechanism of multidrug resistance. Its bipartite structure of two similarly organized halves is explained by a gene fusion event during evolution. However, the clinical significance of this particular feature, if it seemed obvious in the 1980s as a factor producing chemoresistance, is currently revised-being a marker of tumor aggressiveness rather than the cause of drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Chemotherapy induces or increases expression of multidrug resistance-associated protein in malignant melanoma cells.

BACKGROUND: Human malignant melanoma is notoriously resistant to chemotherapeutic agents. Melanoma-derived cell lines are often markedly chemoresistant, suggesting that cellular mechanisms mediate generation of the multidrug resistance (MDR) phenotype. This phenotype is often due to P-glycoprotein (Pgp) and the MDR-associated protein (MRP), which are drug transporter proteins associated with resistance to a broad spectrum of lipophilic drugs. OBJECTIVES: To determine the relationships between the expression of the MDR gene MDR-1 (the product of which is Pgp) or the MRP gene, and clinical chemoresistance of malignant melanoma. METHODS: We examined changes in the expression of MDR-1 and MRP genes at the mRNA level before and after chemotherapy by reverse transcription-polymerase chain reaction (RT-PCR) analysis using formalin-fixed, paraffin-embedded sections of 18 specimens taken from eight melanoma patients. mRNA expression of the MDR-1 and MRP gene-specific PCR products was quantitatively determined by densitometry and compared with that of an internal standard (beta-actin). RESULTS: Five of seven primary melanomas were found to express the MRP gene to a certain extent even before chemotherapy. After first and second courses of chemotherapy, six patients had an increased ratio of MRP mRNA to beta-actin mRNA compared with the prechemotherapy levels in the same patients. None of the cases of melanoma expressed MDR-1. CONCLUSIONS: These results suggest that a significant mRNA level of MRP gene was intrinsically present in malignant melanoma even before exposure to chemotherapeutic drugs and increased in its expression after chemotherapy, suggesting that MRP plays a part in increasing the chemoresistance of malignant melanoma during chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1988

The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus.

A survey of the expression of the multidrug-resistance gene (mdr) in mouse tissues revealed that a mdr mRNA species is expressed at extremely high levels in the gravid uterus. mdr mRNA expression levels increase dramatically during pregnancy compared to the relatively low levels of expression observed in the nongravid uterus. In situ hybridization experiments revealed that the increased expression of the mdr mRNA is specifically localized to the secretory epithelial cells of the endometrium. Immunocytochemistry studies with a mdr glycoprotein-specific antiserum demonstrate that the mdr glycoprotein is predominantly localized to the luminal surface of the secretory epithelial cells. These results indicate that the mdr gene expression in the uterus is controlled by the physiologic changes associated with pregnancy. Our data are consistent with a potential role for the mdr glycoprotein in the transport of substrate across the secretory epithelium of the gravid uterus.

Animals↗

PubMed2002

Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance.

The causes and mechanisms underlying multidrug resistance (MDR) in epilepsy are still elusive and may depend on inadequate drug concentration in crucial brain areas. We studied whether limbic seizures or anticonvulsant drug treatments in rodents enhance the brain expression of the MDR gene (mdr) encoding a permeability glycoprotein (P-gp) involved in MDR to various cancer chemotherapeutic agents. We also investigated whether changes in P-gp levels affect anticonvulsant drug concentrations in the brain. Mdr mRNA measured by RT-PCR increased by 85% on average in the mouse hippocampus 3-24 hr after kainic acid-induced limbic seizures, returning to control levels by 72 hr. Treatment with therapeutic doses of phenytoin or carbamazepine for 7 d did not change mdr mRNA expression in the mouse hippocampus 1-72 hr after the last drug administration. Six hours after seizures, the brain/plasma ratio of phenytoin was reduced by 30% and its extracellular concentration estimated by microdialysis was increased by twofold compared with control mice. Knock-out mice (mdr1a/b -/-) lacking P-gp protein showed a 46% increase in phenytoin concentrations in the hippocampus 1 and 4 hr after injection compared with wild-type mice. A significant 23% increase was found in the cerebellum at 1 hr and in the cortex at 4 hr. Carbamazepine concentrations were measurable in the hippocampus at 3 hr in mdr1a/b -/- mice, whereas they were undetectable at the same time interval in wild-type mice. In rats having spontaneous seizures 3 months after electrically induced status epilepticus, mdr1 mRNA levels were enhanced by 1.8-fold and fivefold on average in the hippocampus and entorhinal cortex, respectively. Thus, changes in P-gp mRNA levels occur in limbic areas after both acute and chronic epileptic activity. P-gp alterations significantly affect antiepileptic drugs concentrations in the brain, suggesting that seizure-induced mdr mRNA expression contributes to MDR in epilepsy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Ribozyme-mediated reversal of the multidrug-resistant phenotype.

This study examined the effects of suppressing c-fos oncogene expression on multidrug resistance (MDR). A2780S human ovarian carcinoma cells with resistance to actinomycin D were isolated and the resultant A2780AD cells exhibited the MDR phenotype. A hammerhead ribozyme designed to cleave fos RNA cloned into the pMAMneo plasmid was transfected into A2780AD cells. Induction of the ribozyme resulted in decreased expression of c-fos, as well as that of the MDR gene (mdr-1), c-jun, and mutant p53. The transformants displayed altered morphology and restored sensitivity to chemotherapeutic agents comprising the MDR phenotype. An anti-mdr ribozyme separately expressed in A2780AD cells efficiently degraded mdr-1 mRNA. However, reversal of the MDR phenotype by the anti-mdr ribozyme occurred one-fourth as rapidly as that induced by the anti-fos ribozyme. These results reinforce the central role played by c-fos in drug resistance through its participation in signal transduction pathways.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Expression of the multidrug resistance gene in human prostate cancer.

Prostate cancer has become the most common cancer in males and the second most common cause of male cancer death in England and Wales. Death rates have doubled over the last 20 years. Prostate cancer is characterized by a high initial response rate to hormonal therapy. Drug-resistance is a significant cause of relapse in cancer. The multidrug resistance genes (MDR) encode resistance to a diverse family of cytotoxic chemotherapy agents. There are four known MDR genes, two of which are present in humans. MDR1 encodes for P-glycoprotein, a 170-kDa transmembrane calcium-dependent efflux pump. We examined P-glycoprotein expression by immunocytochemistry in 96 patients with prostate cancer and 20 patients with benign prostatic hypertrophy. A direct correlate was found between tumor grade, stage, and prostate specific antigen levels, indicating the possible significance of this protein in recurrent prostate cancer.

Journal Article↗

PubMed1989

Expression of the mdr-1/P-170 gene in patients with acute lymphoblastic leukemia.

Increased expression of the multidrug resistance gene (mdr-1/P-170) and the dihydrofolate reductase (DHFR) gene have been implicated in the development of in vitro drug resistance. Overexpression, with or without gene amplification, is seen in the development of drug resistance in culture and it has been postulated that genetic modulation of mdr-1/P-170 and DHFR may also be involved in the development of clinical drug resistance. We screened lymphoblasts from 28 patients with acute lymphoblastic leukemia (ALL) for evidence of overexpression of mdr-1/P-170 using RNAse protection, RNA in situ hybridization and immunohistochemistry. Overexpression of mdr-1/P-170 without gene amplification was detected in samples from four patients (three after multiple relapses, one at presentation). Overexpression of mdr-1/P-170 was heterogeneous within the population of malignant lymphoblasts as demonstrated by RNA in situ hybridization, immunohistochemistry, and drug uptake using daunomycin autofluorescence analysis. There was no evidence of overexpression of DHFR in any of the eight patient samples tested by RNAse protection nor was there any evidence of gene amplification in 11 patient samples on Southern blot analysis. From these observations it appears that overexpression without gene amplification of mdr-1/P-170 may be one mechanism of clinical drug resistance in ALL.

Adolescent↗

PubMed1996

A novel cis-acting element is involved in the promoter activity of the rat mdr1b gene.

Multidrug resistance (MDR) is often associated with overexpression of P-glycoprotein, which is encoded by the mdr gene family. Three mdr genes, i.e., mdr1a (mdr3), mdr1b (mdr1), and mdr2 are present in rodents, and the expression of these genes is temporally and tissue specifically regulated. Furthermore, expression of mdr1b is highly elevated during rat hepatocarcinogenesis. To elucidate how mdr1b expression is regulated, we cloned the genomic sequence of the rat mdr1b gene and functionally dissected its 5' promoter region in various cell lines. The transcription start site identified by the primer extension and RNase protection assays is identical to that of the murine mdr1b homologue. Sequence analysis revealed that the proximal region (within -1300 bp) of the rat mdr1b gene also shares striking similarity to that of the mouse mdr1b gene. Transient transfection assays using reporter gene constructs containing various lengths of the 5' mdr1b sequences revealed that the sequence located between-247 to -126 bp was important for the expression of the reporter gene in many different cell lines. Further analyses revealed that at least one regulatory element located at -189 to -167 bp, which contained the palindromic sequence 5'-AGACATGTCT-3' (-189 to -180 bp), is involved in the promoter function. Gel mobility shift assays demonstrated that this palindromic sequence is essential for specific protein binding. UV cross-linking experiments identified that two major proteins with molecular masses of approximately 41 and 49 kDa were associated with this sequence. A Genbank search and gel motility shift assay competition experiment suggested that the specific binding protein(s) appears to be a novel transcription factor involved in the regulation of the rat mdr1b gene expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Transcription factor c-Jun activation represses mdr-1 gene expression.

Expression of mdr-1 is complex and highly regulated. Several lines of evidence indirectly suggest that transcription factor c-Jun may negatively regulate human mdr-1 gene expression. We recently found that salvicine, a novel topoisomerase II inhibitor, is cytotoxic for multidrug resistance (MDR) tumor cells and down-regulates mdr-1 expression in MDR K562/A02 cells. Salvicine also stimulates a significant increase in the level of c-jun mRNA in HL60 cells. This study investigated the relationship between c-Jun activation and down-regulation of mdr-1 expression by salvicine in K562/A02 cells. Reverse-transcription PCR and Western blotting analyses revealed that salvicine suppressed mdr-1 expression in MDR cells and promoted c-jun expression in both MDR and parental K562 cells. Moreover, levels of c-jun expression were enhanced by salvicine before reduction of mdr-1 expression in K562/A02 cells. Furthermore, c-jun antisense oligodeoxynucleotides prevented salvicine-stimulated enhancement of c-Jun protein and reduction of mdr-1 gene expression, but did not affect the increase in c-jun mRNA levels. Salvicine promoted phosphorylation of c-Jun-N-terminal kinase and c-Jun protein in MDR K562/A02 and parental K562 cells. Electrophoretic mobility shift assay analysis showed that salvicine enhanced DNA binding activity of transcription factor activator protein 1. Additionally, c-jun antisense oligodeoxynucleotides also inhibited salvicine-induced apoptosis and cytotoxicity in MDR and parental K562 cells. A possible pathway emerges from these results: salvicine stimulates c-Jun-N-terminal kinase phosphorylation and activation, resulting in c-Jun phosphorylation and activation. Activated c-Jun promotes expression of c-jun itself, represses mdr-1 transcription, and triggers pro-apoptotic signals, resulting in low mdr-1 expression and cell death. The present results demonstrate that transcription factor c-Jun plays a principal role in down-regulation of mdr-1 expression and induction of apoptosis in salvicine-treated human MDR K562/A02 cells, providing new insights into the complicated mechanisms regulating mdr-1 expression. The findings also suggest that c-Jun might be a potential drug target for circumventing tumor MDR.

Apoptosis↗

PubMed1997

[Clinical significance of expression of multidrug resistance gene in breast cancer tissue].

OBJECTIVES: To investigate the role of expression of multidrug resistance gene (mdr-1 gene) in chemotherapeutic resistance of breast cancer and to determine if expression of mdr-1 gene may act as an index for predicting chemotherapy response and prognosis. METHODS: Using reverse transcription-polymerase chain reaction (RT-PCR) technique, we determined the levels of mdr-1 mRNA in 82 breast cancer samples. RESULTS: Positive expressions of mdr-1 gene were 34.3% in 35 cases of untreated primary breast cancer and 59.0% in 47 cases of relapsed metastatic breast cancer, separately, and the difference was statistically significant (P < 0.05). In 28 cases of relapsed metastatic breast cancer of mdr-1 gene positive expression, 22(78.6%) were ever treated with MDR related drugs. Levels of mdr-1 gene expression of all 7 cases were higher after chemotherapy than before chemotherapy. Positive expressions were 16.7% and high grade positive expressions were 5.6% in 18 sensitive cases. Positive expressions were 71.4% and high grade positive expressions were 50.0% in 14 resistant cases. The difference was statistically significant (P < 0.01). There were no relations between expression of mdr-1 gene and ages, menopause status, lymphnode involvements, clinical stages, and estrogen receptor levels. CONCLUSION: The results indicated that retreated metastatic breast cancer is more extensively resistant than untreated primary breast cancer and acquired drug resistance is an important reason. Expression of mdr-1 gene seems to be a reference index for predicting response of chemotherapy.

Antineoplastic Agents↗

PubMed1997

Gene rearrangement: a novel mechanism for MDR-1 gene activation.

Drug resistance, a major obstacle to cancer chemotherapy, can be mediated by MDR-1/P-glycoprotein. Deletion of the first 68 residues of MDR-1 in an adriamycin-selected cell line after a 4;7 translocation, t(4q;7q), resulted in a hybrid mRNA containing sequences from both MDR-1 and a novel chromosome 4 gene. Further selection resulted in amplification of a hybrid gene. Expression of the hybrid mRNA was controlled by the chromosome 4 gene, providing a model for overexpression of MDR-1. Additional hybrid mRNAs in other drug-selected cell lines and in patients with refractory leukemia, with MDR-1 juxtaposed 3' to an active gene, establishes random chromosomal rearrangements with overexpression of hybrid MDR-1 mRNAs as a mechanism of acquired drug resistance.

Amino Acid Sequence↗

PubMed1994

[The amplification and overexpression of mdr-family genes in ethidium bromide-resistant Chinese hamster CHO-K1 cells and in the hybrids of sensitive and resistant cells].

Stable mutant cells Cebr-1 and Cebr-2, resistant to ethidium bromide (EB) in concentration of 2 micrograms/ml, have been isolated by a multistep selection in Chinese hamster ovary cells. It was shown that Cebr-1 and Cebr-2 cells acquired a cross-resistance to unrelated drugs. Stable changes in the structure of chromosomes 1, 2, 5 and 8 were revealed by karyological analysis. Overexpression and amplification of mdr genes were detected in Cebr-2 cells using Northern RNA and Southern DNA blot hybridization. Two independent hybrids Hybr-1 and Hybr-2 were obtained by fusion of Cebr-2 cells with Chinese hamster lung V-79 RJK cells, sensitive to EB. Hybr-2 cells were characterized by the same level of EB-resistance as Cebr-2 cells. Hybr-1 cells have a lower level of EB-resistance than Cebr-2 cells. Hybr-2 cells have demonstrated amplification and overexpression of mdr gene, the same as in Cebr-2 cells, whereas in Hybr-1 cells no mdr gene amplification was observed, but the level of mdr gene expression was higher than in sensitive cells. The data suggest that resistance of Chinese hamster cells to EB is mediated by amplification and overexpression of mdr genes.

Animals↗

PubMed2000

Decitabine (5-Aza-2'-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells.

Multidrug resistance (MDR) is a major problem in patients with hematological malignancies. Although drug-resistance is known to be induced by the expression of P-glycoprotein (P-gp) encoded by the MDR-1 gene, little is known about the mechanisms regulating this gene. Herein, we studied the DNA methylation patterns at the enhancer and repressor binding sites of the MDR-1 gene using the human erythroleukemia cell line K562 and its multidrug resistant derivative K562/ADM (adriamycin). Direct DNA sequence analysis demonstrated methylation to be present at the repressor site (minus 110 GC-box) of the MDR-1 gene in K562/ADM cells, but not in parental K562 cells. Methylation-specific PCR (MSP) analysis yielded similar results. Treatment of K562/ADM cells with 5-Aza-2'-deoxycytidine (decitabine; DAC), an inhibitor of DNA methyltransferase, caused demethylation of the repressor binding site of MDR-1 gene, as assessed by MSP, and also decreased P-gp expression, as assessed by flow cytometric and Northern blot analysis. Although it is generally accepted that DAC upregulates gene expression by demethylating the activator binding sites, our present results suggest that DAC induces down-regulation of P-gp expression as a result of demethylation at the repressor binding site in K562/ADM cells. In this regard, methylation-dependent regulation of the MDR-1 gene in K562/ADM cells is unique.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Modulation of the mdr-1b gene in the kidney of rats subjected to dehydration or a high-salt diet.

The localization of the multidrug resistance gene (mdr-1b) messenger ribonucleic acid (mRNA) along the rat nephron and its regulation was investigated under two different experimental situations: dehydration and high-Na+ diet. The mdr-1b mRNA was detected in glomeruli, proximal tubule segments, cortical and medullary thick ascending limbs, inner medullary collecting ducts and thin limbs of Henle's loop. Using the ribonuclease (RNase) protection assay (RPA), the abundance of mdr-1b mRNA was shown to be 35% less in renal cortex than in medulla. The mdr-1b mRNA expression in dehydrated rats in cortex or medulla did not differ from control. However, after 5 or 14 days on a high-Na+ diet, mdr-1b expression had decreased significantly in both cortex and medulla. There was no change in protein expression in dehydrated rats but a significant decrease occurred in rats fed the high-salt diet, confirming the results obtained with RPA. Our results suggest that the mdr-1b product is involved in extracellular volume regulation in rats.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1997

Altered expression and function of P-glycoprotein (170 kDa), encoded by the MDR 1 gene, in T cell subsets from aging humans.

Aging is associated with progressive T cell-mediated immune deficiency, increased frequency of infections, and autoimmune phenomena. P-glycoprotein (P-gP), a 170-kDa glycoprotein, is a member of a superfamily of ATP-binding cassette transport proteins that has been shown to express on cells of the immune system and suggested to play a role in secretion of certain cytokines and cytotoxic molecules. Because aging is associated with altered secretion of cytokines, in this investigation we examined the expression and function of P-gP in CD4+ and CD8+ T cells and their "memory" and "naïve" subpopulations in peripheral blood from healthy aging and young subjects. P-glycoprotein expression was analyzed at the protein levels by dual- or triple-color flow cytometric analysis, using monoclonal antibodies against P-gP (MRK16), and at the mRNA level by quantitative reverse-transcriptase polymerase chain reaction. The efflux function of P-gP was measured by intracellular accumulation of rhodamine-123 (Rh123; a substrate for P-gP) in the presence or absence of cyclosporin A (which binds to P-gP and inhibits its efflux function). The data show increased expression of P-gP at both the protein and the mRNA levels in aging lymphocytes. Increased P-gP expression, at the protein level, was also observed in naïve cell subpopulations from aging CD4+ and CD8+ T cell subsets compared to those from young controls. An increase in P-gP function, as measured by the ability of T cell subsets to efflux Rh123, was observed in aging CD4+ and CD8+ T cell subsets and their naïve and memory subpopulations. These data suggest that altered P-gP expression and function in aging may play a role in changes in immune response, including cytokine secretion, associated with human aging.

ATP Binding Cassette Transporter, Subfamily B, Mem↗