Chemosensitizing multiple drug resistance of human carcinoma by bicyclol involves attenuated P-glycoprotein, GST-P and Bcl-2

Colchicine-resistant Chinese hamster ovary (CHO) cell mutants whose resistance results from reduced drug permeability have been isolated previously in our laboratories. This reduced permeability affects a wide range of unrelated drugs, resulting in the mutants displaying a multiple drug resistance phenotype. A 170,000-dalton cell surface glycoprotein (P-glycoprotein) was identified, and its expression appears to correlate with the degree of resistance. In this study we were able to confer the multiple drug resistance phenotype on sensitive mouse L cells by DNA-mediated gene transfer of DNA obtained from the colchicine-resistant mutants. P-glycoprotein was detected in plasma membranes of these DNA transformants by staining with an antiserum raised against membranes of mutant CHO cells. These results are consistent with a causal relationship between P-glycoprotein expression and the multiple drug resistance phenotype.

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DNA-mediated transfer of multiple drug resistance and plasma membrane glycoprotein expression

Molecular and Cellular Biology ◽

10.1128/mcb.2.8.881-889.1982 ◽

1982 ◽

Vol 2 (8) ◽

pp. 881-889

Author(s):

P G Debenham ◽

N Kartner ◽

L Siminovitch ◽

J R Riordan ◽

V Ling

Keyword(s):

Drug Resistance ◽

Plasma Membranes ◽

Multiple Drug Resistance ◽

Chinese Hamster ◽

Surface Glycoprotein ◽

Multiple Drug ◽

Cell Surface Glycoprotein ◽

Resistance Phenotype ◽

P Glycoprotein ◽

Wide Range

Colchicine-resistant Chinese hamster ovary (CHO) cell mutants whose resistance results from reduced drug permeability have been isolated previously in our laboratories. This reduced permeability affects a wide range of unrelated drugs, resulting in the mutants displaying a multiple drug resistance phenotype. A 170,000-dalton cell surface glycoprotein (P-glycoprotein) was identified, and its expression appears to correlate with the degree of resistance. In this study we were able to confer the multiple drug resistance phenotype on sensitive mouse L cells by DNA-mediated gene transfer of DNA obtained from the colchicine-resistant mutants. P-glycoprotein was detected in plasma membranes of these DNA transformants by staining with an antiserum raised against membranes of mutant CHO cells. These results are consistent with a causal relationship between P-glycoprotein expression and the multiple drug resistance phenotype.

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Co-amplification of double minute chromosomes, multiple drug resistance, and cell surface P-glycoprotein in DNA-mediated transformants of mouse cells

Molecular and Cellular Biology ◽

10.1128/mcb.4.3.500-506.1984 ◽

1984 ◽

Vol 4 (3) ◽

pp. 500-506

Author(s):

S M Robertson ◽

V Ling ◽

C P Stanners

Keyword(s):

Drug Resistance ◽

Multiple Drug Resistance ◽

Resistant Mutant ◽

Genetic System ◽

Cell Membrane Permeability ◽

Multiple Drug ◽

P Glycoprotein ◽

Double Minute ◽

Mouse Cells ◽

Double Minute Chromosomes

A genetic system comprised of mammalian cell mutants which demonstrate concomitant resistance to a number of unrelated drugs has been described previously. The resistance is due to reduced cell membrane permeability and is correlated with the presence of large amounts of a plasma membrane glycoprotein termed P-glycoprotein. This system could represent a model for multiple drug resistance which develops in cancer patients treated with chemotherapeutic drugs. We demonstrate here that the multiple drug resistance phenotype can be transferred to mouse cells with DNA from a drug-resistant mutant and then amplified quantitatively by culture in media containing increasing concentrations of drug. The amount of P-glycoprotein was correlated directly with the degree of drug resistance in the transformants and amplified transformants. In addition, the drug resistance and expression of P-glycoprotein of the transformants were unstable and associated quantitatively with the number of double minute chromosomes. We suggest that the gene for multiple drug resistance and P-glycoprotein is contained in these extrachromosomal particles and is amplified by increases in double minute chromosome number. The potential use of this system for manipulation of mammalian genes in general is discussed.

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Immunohistochemical Estimates of Angiogenesis, Proliferative Activity, p53 Expression, and Multiple Drug Resistance Have No Prognostic Impact in Osteosarcoma: A Comparative Clinicopathological Investigation

Sarcoma ◽

10.1155/2008/874075 ◽

2008 ◽

Vol 2008 ◽

pp. 1-14 ◽

Cited By ~ 10

Author(s):

Flemming Brandt Sorensen ◽

Kenneth Jensen ◽

Michael Vaeth ◽

Henrik Hager ◽

Anette Mariane Daa Funder ◽

...

Keyword(s):

Drug Resistance ◽

Proliferative Activity ◽

Multiple Drug Resistance ◽

Multiple Drug ◽

Prognostic Impact ◽

Prognostic Variables ◽

P53 Expression ◽

P Glycoprotein ◽

Sufficient Power ◽

Mib 1

Purpose. To investigate angiogenesis, multiple drug resistance (MDR) and proliferative activity as prognostic variables in patients suffering from osteosarcoma.Methods. Histologic biopsies from 117 patients treated in the period from 1972 through 1999 were immunohistologically investigated regarding angiogenesis (CD34), proliferative activity (MIB-1), and the expression of p53 and MDR (P-glycoprotein (Pgp); clones JSB-1, C494, and MRK16). Quantitative and semiquantitative scores of immunoreactive cells were analyzed statistically along with retrospectively obtained clinicopathologic variables.Results. Chemotherapy reduced the rate of amputations (P=.00002). The Pgp was overexpressed (score ≥2) in 48% of the primary, diagnostic biopsies, and high Pgp correlated with high Pgp in postsurgical specimens (P=.003). In contrast, no such associations were disclosed for estimates of angiogenesis (P=.64) and p53 (P>.32), whereas the MIB-1 index was reduced in the post-chemotherapy specimens (P=.02). The overall, disease-specific survival was 47%, increasing to 54% in patients receiving pre-operative chemotherapy. Statistical analyses showed prognostic impact exclusively by patient age and type of osteosarcoma.Discussion. The studied series of patients documented already prior to the chemotherapy era, a rather excellent survival and estimates of angiogenesis, proliferation, p53, and Pgp expressions, did not demonstrate sufficient power to serve as predictors of treatment response or survival.

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The MDR1 (P-glycoprotein) and MRP (P-190) transporters do not play a major role in the intrinsic multiple drug resistance of Jurkat T lymphocytes

Leukemia Research ◽

10.1016/s0145-2126(97)00063-5 ◽

1997 ◽

Vol 21 (11-12) ◽

pp. 1077-1086 ◽

Cited By ~ 7

Author(s):

Julie Martel ◽

Marcel D. Payet ◽

Gilles Dupuis

Keyword(s):

Drug Resistance ◽

T Lymphocytes ◽

Multiple Drug Resistance ◽

Multiple Drug ◽

P Glycoprotein

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S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation

International Journal of Molecular Sciences ◽

10.3390/ijms22179286 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9286

Author(s):

Laura Mosca ◽

Martina Pagano ◽

Luigi Borzacchiello ◽

Luigi Mele ◽

Annapina Russo ◽

...

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Defense Mechanism ◽

Multiple Drug Resistance ◽

Nutritional Supplement ◽

Multi Drug Resistance ◽

Multiple Drug ◽

Cell Defense ◽

P Glycoprotein

Colorectal cancer (CRC) is the second deadliest cancer worldwide despite significant advances in both diagnosis and therapy. The high incidence of CRC and its poor prognosis, partially attributed to multi-drug resistance and antiapoptotic activity of cancer cells, arouse strong interest in the identification and development of new treatments. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and proapoptotic effects as well as for its potential in overcoming drug resistance in many kinds of human tumors. Here, we report that AdoMet enhanced the antitumor activity of 5-Fluorouracil (5-FU) in HCT 116p53+/+ and in LoVo CRC cells through the inhibition of autophagy, induced by 5-FU as a cell defense mechanism to escape the drug cytotoxicity. Multiple drug resistance is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). We demonstrate here that AdoMet was able to revert the 5-FU-induced upregulation of P-gp expression and to decrease levels of acetylated NF-κB, the activated form of NF-κB, the major antiapoptotic factor involved in P-gp-related chemoresistance. Overall, our data show that AdoMet, was able to overcome 5-FU chemoresistance in CRC cells by targeting multiple pathways such as autophagy, P-gp expression, and NF-κB signaling activation and provided important implications for the development of new adjuvant therapies to improve CRC treatment and patient outcomes.

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