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

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.

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Overcoming multidrug-resistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416

Bioscience Reports ◽

10.1042/bsr20120020 ◽

2012 ◽

Vol 32 (6) ◽

pp. 559-566 ◽

Cited By ~ 19

Author(s):

Yan Xu ◽

Feng Zhi ◽

Guangming Xu ◽

Xiaolei Tang ◽

Sheng Lu ◽

...

Keyword(s):

Multidrug Resistance ◽

Cancer Chemotherapy ◽

Antitumour Activity ◽

Multidrug Resistant ◽

The Novel ◽

Mice Model ◽

P Glycoprotein ◽

Channel Currents

MDR (multidrug-resistance) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by overexpression of P-gp (P-glycoprotein). Much effort has been devoted to developing P-gp inhibitors to modulate MDR. However, none of the inhibitors on the market have been successful. 1416 [1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (phenoprolamine hydrochloride)] is a new VER (verapamil) analogue with a higher IC50 for blocking calcium channel currents than VER. In the present paper, we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of VBL (vinblastine) in P-gp-overexpressed human multidrug-resistant K562/ADM (adriamycin) and KBV cells, but had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rh123 (rhodanmine123) content in MDR cells. Human K562/ADM xenograft-nude mice model verified that 1416 potentiates the antitumour activity of VBL in vivo. RT-PCR (reverse transcriptase-PCR) and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggest that 1416 could be a promising agent for overcoming MDR in cancer chemotherapy.

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Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo

Cancer Letters ◽

10.1016/j.canlet.2018.10.020 ◽

2019 ◽

Vol 442 ◽

pp. 91-103 ◽

Cited By ~ 9

Author(s):

Albert A. De Vera ◽

Pranav Gupta ◽

Zining Lei ◽

Dan Liao ◽

Silpa Narayanan ◽

...

Keyword(s):

Multidrug Resistance ◽

Glycoprotein P ◽

P Glycoprotein

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Imaging Gene Expression in Cancer: Functional Identification of Multidrug Resistance P-glycoprotein In Vivo

Diagnostic Nuclear Medicine ◽

10.1007/978-3-662-06590-7_16 ◽

2000 ◽

pp. 273-283

Author(s):

D. Piwnica-Worms ◽

G. D. Luker ◽

K. E. Luker ◽

V. V. Rao ◽

V. Sharma

Keyword(s):

Gene Expression ◽

Multidrug Resistance ◽

Functional Identification ◽

P Glycoprotein ◽

Imaging Gene Expression

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HZ08 Reverse P-Glycoprotein Mediated Multidrug Resistance In Vitro and In Vivo

PLoS ONE ◽

10.1371/journal.pone.0116886 ◽

2015 ◽

Vol 10 (2) ◽

pp. e0116886 ◽

Cited By ~ 6

Author(s):

Zheyi Hu ◽

Zaigang Zhou ◽

Yahui Hu ◽

Jinhui Wu ◽

Yunman Li ◽

...

Keyword(s):

Multidrug Resistance ◽

P Glycoprotein

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Is P-Glycoprotein a Sufficient Marker for Multidrug Resistance in Vivo? Immunohistochemical Staining for P-Glycoprotein in Children and Adult Leukemia: Correlation with Clinical Outcome

Leukemia & Lymphoma ◽

10.3109/10428199509054766 ◽

1995 ◽

Vol 20 (1-2) ◽

pp. 143-152 ◽

Cited By ~ 5

Author(s):

Slawomir Kaczorowski ◽

Maria Ochocka ◽

Maria Kaczorowska ◽

Robert Aleksandrowicz ◽

Micha Matysiakl ◽

...

Keyword(s):

Multidrug Resistance ◽

Clinical Outcome ◽

Immunohistochemical Staining ◽

P Glycoprotein ◽

Adult Leukemia

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P-glycoprotein-mediated acquired multidrug resistance of human lung cancer cells in vivo

British Journal of Cancer ◽

10.1038/bjc.1996.655 ◽

1996 ◽

Vol 74 (12) ◽

pp. 1929-1934 ◽

Cited By ~ 16

Author(s):

Y Abe ◽

Y Ohnishi ◽

M Yoshimura ◽

E Ota ◽

Y Ozeki ◽

...

Keyword(s):

Lung Cancer ◽

Multidrug Resistance ◽

Cancer Cells ◽

Human Lung ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

P Glycoprotein ◽

Human Lung Cancer Cells

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

Biochemical Society Transactions ◽

10.1042/bst0381537 ◽

2010 ◽

Vol 38 (6) ◽

pp. 1537-1542 ◽

Cited By ~ 7

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.

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Determination of multidrug resistance in vivo by monoclonal antibodies against P-glycoprotein in an MDR-1 transfected melanoma cell line

European Journal of Cancer and Clinical Oncology ◽

10.1016/0277-5379(90)90698-s ◽

1990 ◽

Vol 26 (9) ◽

pp. 1015

Keyword(s):

Monoclonal Antibodies ◽

Multidrug Resistance ◽

Cell Line ◽

Melanoma Cell ◽

Melanoma Cell Line ◽

P Glycoprotein ◽

Mdr 1

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Reversal of P-glycoprotein-medicated multidrug resistance by LBM-A5 in vitro and a study of its pharmacokinetics in vivo

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0377 ◽

2015 ◽

Vol 93 (1) ◽

pp. 33-38 ◽

Cited By ~ 4

Author(s):

Tianxiao Zhao ◽

Yun Song ◽

Baomin Liu ◽

Qianqian Qiu ◽

Lei Jiao ◽

...

Keyword(s):

Multidrug Resistance ◽

Cancer Chemotherapy ◽

Anticancer Agents ◽

Efflux Pump ◽

Therapeutic Index ◽

Intracellular Accumulation ◽

P Glycoprotein ◽

Reversal Mechanism

The overexpression of P-glycoprotein (P-gp) in tumors leads to multidrug resistance (MDR), which is a significant obstacle in clinical cancer chemotherapy. The co-administration of anticancer drugs and MDR modulators is a promising strategy for overcoming this problem. Our study aimed to explore the reversal mechanism and safety of the MDR modulator LBM-A5 in vitro, and evaluate its pharmacokinetics and effects on doxorubicin metabolism in vivo. We evaluated an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of anticancer agents mediated by LBM-A5, the effect of LBM-A5 on rhodamine123 intracellular accumulation, and the efflux in K562/DOX cells to investigate the reversal mechanisms of LBM-A5. The results showed that LBM-A5 inhibits rhodamine123 efflux and increases intracellular accumulation by inhibiting the efflux pump function of P-gp. Furthermore, the therapeutic index and CYP3A4 activity analysis in vitro suggested that LBM-A5 is reasonably safe to use. Also, LBM-A5 (10 mg/kg body mass) achieved the required plasma concentration in sufficient time to reverse MDR in vivo. Importantly, the LBM-A5 treatment group shared similar doxorubicin (DOX) pharmacokinetics with the free DOX group. Our results suggest that LBM-A5 effectively reverses MDR (EC50 = 483.6 ± 81.7 nmol·L−1) by inhibiting the function of P-gp, with relatively ideal pharmacokinetics and in a safe manner, and so may be a promising candidate for cancer chemotherapy research.

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