Modulation of Multidrug-Resistance-Associated P-Glycoprotein in Human U-87 MG and HUV-ECC Cells with Antisense Oligodeoxynucleotides to MDR1 mRNA

Pathobiology ◽  
2004 ◽  
Vol 71 (3) ◽  
pp. 123-128 ◽  
Author(s):  
Marion Rittierodt ◽  
Thomas Tschernig ◽  
Kunyu Harada
Keyword(s):  
Multidrug Resistance ◽  
Antisense Oligodeoxynucleotides ◽  
P Glycoprotein ◽  
Mdr1 Mrna

Escape from stress granule sequestration: another way to drug resistance?

2010 ◽  
Vol 38 (6) ◽  
pp. 1537-1542 ◽  
Author(s):  
Ernesto Yagüe ◽  
Selina Raguz
Keyword(s):  
Endoplasmic Reticulum ◽  
Multidrug Resistance ◽  
Stress Granules ◽  
Stress Granule ◽  
Chemotherapeutic Drugs ◽  
P Glycoprotein ◽  
Mdr1 Mrna ◽  
Leukaemic Cells ◽  
Multidrug Resistance 1 Gene ◽  
Polysome Profile

Overexpression of P-glycoprotein, encoded by the MDR1 (multidrug resistance 1) gene, is often responsible for multidrug resistance and chemotherapy failure in cancer. We have demonstrated that, in leukaemic cells, P-glycoprotein expression is regulated at the translational level. More recently, we have shown that in cells overexpressing P-glycoprotein, MDR1 mRNA does not aggregate into translationally silent stress granules. Importantly, this is not unique for MDR1, since other transcripts encoding transmembrane proteins, and which are thus translated at the endoplasmic reticulum, follow the same pattern. By using a series of chimaeric transcripts, we have demonstrated that transcript localization at the endoplasmic reticulum bypasses the signals dictating stress granule sequestration. Polysome profile analyses and protein synthesis experiments indicate that, upon stress withdrawal, endoplasmic-reticulum-bound transcripts resume translation faster than those at the cytosol, which have been sequestered into stress granules. This may represent a novel mechanism by which drug-resistant cells respond quickly to stress, helping them to survive the cytotoxic effect of chemotherapeutic drugs.

scholarly journals Role of the highly structured 5′-end region of MDR1 mRNA in P-glycoprotein expression

2007 ◽  
Vol 406 (3) ◽  
pp. 445-455 ◽  
Author(s):  
Rebecca A. Randle ◽  
Selina Raguz ◽  
Christopher F. Higgins ◽  
Ernesto Yagüe
Keyword(s):  
Multidrug Resistance ◽  
Drug Exposure ◽  
Cytotoxic Drugs ◽  
Initiation Factor ◽  
Mrna Levels ◽  
Translational Repressor ◽  
P Glycoprotein ◽  
Mdr1 Mrna ◽  
Cytotoxic Stress

Overexpression of P-glycoprotein, encoded by the MDR1 (multidrug resistance 1) gene, is often responsible for multidrug resistance in acute myeloid leukaemia. We have shown previously that MDR1 (P-glycoprotein) mRNA levels in K562 leukaemic cells exposed to cytotoxic drugs are up-regulated but P-glycoprotein expression is translationally blocked. In the present study we show that cytotoxic drugs down-regulate the Akt signalling pathway, leading to hypophosphorylation of the translational repressor 4E-BP [eIF (eukaryotic initiation factor) 4E-binding protein] and decreased eIF4E availability. The 5′-end of MDR1 mRNA adopts a highly-structured fold. Fusion of this structured 5′-region upstream of a reporter gene impeded its efficient translation, specifically under cytotoxic stress, by reducing its competitive ability for the translational machinery. The effect of cytotoxic stress could be mimicked in vivo by blocking the phosphorylation of 4E-BP by mTOR (mammalian target of rapamycin) using rapamycin or eIF4E siRNA (small interfering RNA), and relieved by overexpression of either eIF4E or constitutively-active Akt. Upon drug exposure MDR1 mRNA was up-regulated, apparently stochastically, in a small proportion of cells. Only in these cells could MDR1 mRNA compete successfully for the reduced amounts of eIF4E and translate P-glycoprotein. Consequent drug efflux and restoration of eIF4E availability results in a feed-forward relief from stress-induced translational repression and to the acquisition of drug resistance.

Modulation of Multidrug Resistance Gene (mdr-1) with Antisense Oligodeoxynucleotides

1996 ◽  
Vol 91 (1) ◽  
pp. 93-98 ◽  
Author(s):  
Chao Liu ◽  
Imran Ahmad Qureshi ◽  
Xun-Jie Ding ◽  
Yi-Fei Shan ◽  
Yi-Wei Huang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Multidrug Resistant ◽  
Polymerase Chain Reaction Method ◽  
Antisense Oligodeoxynucleotides ◽  
Multidrug Resistance Gene ◽  
Glycoprotein Synthesis ◽  
P Glycoprotein ◽  
Anti Cancer ◽  
Initiator Codon ◽  
Mdr 1

1. Multidrug resistance is the major obstacle to successful cancer chemotherapy. Circumventing multidrug resistance therefore represents a high priority for clinical anti-cancer treatment. Among many reversal strategies, antisense oligodeoxynucleotides may offer a molecular targeting tool for overcoming cellular multidrug resistance. 2. Two 17-mer phosphorothioate antisense oligomers, complementary to the 5′ end of the ATG initiator codon-containing region and loop-forming site (located at nucleotides 991–1007 from the first ATG codon) in mdr-1 cDNA sequence, were synthesized. The purpose was to study their effects on the function and expression of P-glycoprotein and mdr-1 gene. 3. The results showed that 10 μmol/l antisense oligomers could significantly inhibit the growth of multidrug resistant K562/Adm cells cultured in adriamycin-containing medium. No such effect was observed for parental (sensitive) K562/S cells. Intracellular daunorubicin accumulation increased greatly in the K562/Adm cells after they were treated with oligomers for 48 h and P-glycoprotein synthesis was strikingly reduced. 4. Further investigation with [α-32P]dCTP incorporation by the reverse transcriptase—polymerase chain reaction method revealed that antisense oligomers could result in a reduction in the level of mdr-1 mRNA, probably through hindering mdr-1 gene transcription. 5. The high reversal efficiency and specificity of antisense oligomers in regulating mdr-1 gene expression suggest a potential clinical application in gene therapy for drug resistant malignancies.

Induction of multidrug resistance in MOLT-4 cells by anticancer agents is closely related to increased expression of functional P-glycoprotein and MDR1 mRNA

2002 ◽  
Vol 49 (5) ◽  
pp. 391-397 ◽  
Author(s):  
Zhen-Li Liu ◽  
Kenji Onda ◽  
Sachiko Tanaka ◽  
Tsugutoshi Toma ◽  
Toshihiko Hirano ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Anticancer Agents ◽  
P Glycoprotein ◽  
Mdr1 Mrna

Multidrug resistance inhibition by antisense oligonucleotide against MDR1/mRNA in P-glycoprotein expressing leukemic cells

Hematology ◽  
2007 ◽  
Vol 12 (5) ◽  
pp. 393-401 ◽  
Author(s):  
Fatemeh Nadali ◽  
Ali-Akbar Pourfathollah ◽  
Kamran Alimoghaddam ◽  
Mahin Nikougoftar ◽  
Shahrbano Rostami ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Antisense Oligonucleotide ◽  
Leukemic Cells ◽  
P Glycoprotein ◽  
Mdr1 Mrna

Transfection with Protein Kinase Cα Confers Increased Multidrug Resistance to MCF-7 Cells Expressing P-Glycoprotein

1991 ◽  
Vol 3 (6) ◽  
pp. 181-189 ◽  
Author(s):  
Gang Yu ◽  
Shakeel Ahmad ◽  
Angelo Aquino ◽  
Craig R. Fairchild ◽  
Jane B. Trepel ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Protein Kinase ◽  
P Glycoprotein ◽  
Protein Kinase Cα ◽  
Mcf 7

scholarly journals Modulation of the expression of a multidrug resistance gene (mdr-1/P-glycoprotein) by differentiating agents

1989 ◽  
Vol 264 (30) ◽  
pp. 18031-18040
Author(s):  
L A Mickley ◽  
S E Bates ◽  
N D Richert ◽  
S Currier ◽  
S Tanaka ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Resistance Gene ◽  
Multidrug Resistance Gene ◽  
P Glycoprotein ◽  
Differentiating Agents ◽  
Mdr 1
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