Human hepatocellular carcinoma cell lines exhibit multidrug resistance unrelated to MRD1 gene expression

1991 ◽  
Vol 98 (3) ◽  
pp. 317-322
Author(s):  
D.W. Shen ◽  
Y.G. Lu ◽  
K.V. Chin ◽  
I. Pastan ◽  
M.M. Gottesman
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Cell Lines ◽  
Actinomycin D ◽  
Efflux Pump ◽  
Mdr1 Gene ◽  
Drug Efflux ◽  
P Glycoprotein ◽  
Drug Efflux Pump

Multidrug resistance of human cancer cells may result from expression of P-glycoprotein, the product of the MRD1 gene, acting as an energy-dependent drug efflux pump. However, direct evidence that expression of the MDR1 gene contributes to the multidrug resistance of human liver carcinomas has not been established. In this study, we tested five cell lines derived from human hepatocellular carcinomas for sensitivity to a variety of drugs used widely as anticancer agents; these included vinblastine, doxorubicin, actinomycin D, mitomycin C, 5-fluorouracil, 6-mercaptopurine, melphalan, methotrexate, cis-platinum and etoposide (VP-16). All five hepatoma cell lines were resistant at different levels to these chemicals compared to human KB cells. Although it has been demonstrated that resistance to vinblastine, colchicine, doxorubicin and actinomycin D in human multidrug-resistant cells is associated with overexpression of P-glycoprotein, very little expression of P-glycoprotein was found in these human hepatoma cells. Neither verapamil nor quinidine, inhibitors of the drug efflux pump, were able to overcome multidrug resistance in hepatoma cells. These results indicate that the multidrug resistance phenotype in human hepatocellular carcinoma cells cannot be attributed to expression of the MDR1 gene, but that novel mechanisms may account for the resistance of these cancer cells.

P-glycoprotein drug efflux pump involved in the mechanisms of intrinsic drug resistance in various colon cancer cell lines

1991 ◽  
Vol 41 (3) ◽  
pp. 349-359 ◽  
Author(s):  
Ellen C. Spoelstra ◽  
Henk Dekker ◽  
Gerrit Jan Schuurhuis ◽  
Henricus J. Broxterman ◽  
Jan Lankelma
Keyword(s):  
Colon Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Efflux Pump ◽  
Colon Cancer Cell ◽  
Drug Efflux ◽  
P Glycoprotein ◽  
Colon Cancer Cell Lines ◽  
Intrinsic Drug Resistance ◽  
Drug Efflux Pump

scholarly journals Lectin detection of cell surface saccharides remodeling induced by development of P-glycoprotein mediated multidrug resistance phenotype in L1210 leukemia cells

2014 ◽  
Vol 7 (1) ◽  
pp. 52-56 ◽  
Author(s):  
Mário Šereš ◽  
Lucia Pavlíková ◽  
Zdena Sulová ◽  
Albert Breier
Keyword(s):  
Multidrug Resistance ◽  
Cell Surface ◽  
Efflux Pump ◽  
L1210 Cell ◽  
Leukemia Cells ◽  
Drug Efflux ◽  
L1210 Leukemia ◽  
P Glycoprotein ◽  
Drug Efflux Pump ◽  
State Of Art

Abstract P-glycoprotein is an ATP dependent drug efflux pump the expression of which is responsible for strong depression of cell sensitivities to large group of structurally unrelated substances in neoplastic cells. We found that the expression of this protein in mice leukemia cells L1210 is associated with massive remodeling of cell surface saccharides. This remodeling is consistent with the alteration of cellular contents of UDP-sugars, glycogen and glycoproteins when P-gp positive and P-gp negative L1210 cell variants were compared. The current paper is focused on bringing the state of art information about this topic.

P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells

Life Sciences ◽  
1992 ◽  
Vol 51 (18) ◽  
pp. 1427-1437 ◽  
Author(s):  
Akira Tsuji ◽  
Tetsuya Terasaki ◽  
Yasushi Takabatake ◽  
Yoshiyuki Tenda ◽  
Ikumi Tamai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Efflux Pump ◽  
Bovine Brain ◽  
Drug Efflux ◽  
Brain Capillary ◽  
Brain Capillary Endothelial Cells ◽  
P Glycoprotein ◽  
Capillary Endothelial Cells ◽  
Drug Efflux Pump

Mechanisms of TPGS and its derivatives inhibiting P-glycoprotein efflux pump and application for reversing multidrug resistance in hepatocellular carcinoma

2018 ◽  
Vol 9 (14) ◽  
pp. 1827-1839 ◽  
Author(s):  
Tengfei Liu ◽  
Xiaoyan Liu ◽  
Hui Xiong ◽  
Cheng Xu ◽  
Jianxu Yao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multidrug Resistance ◽  
Negative Charge ◽  
Efflux Pump ◽  
P Glycoprotein

We have developed a TPGS–GA conjugate and TPGS–LA conjugate which possess more effective P-gp inhibition compared to TPGS because of the enhancement of hydrophilicity and negative charge.

Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells

1999 ◽  
Vol 277 (1) ◽  
pp. F84-F96 ◽  
Author(s):  
Shinya Ito ◽  
Cindy Woodland ◽  
Balázs Sarkadi ◽  
Guido Hockmann ◽  
Scott E. Walker ◽  
...  
Keyword(s):  
Drug Transport ◽  
Diffusion Processes ◽  
Efflux Pump ◽  
Mdck Cells ◽  
Basolateral Membrane ◽  
Drug Efflux ◽  
Drug Transfer ◽  
P Glycoprotein ◽  
Drug Efflux Pump ◽  
Apical Membranes

P-glycoprotein (P-gp) on the apical membranes of epithelial cells is known as a drug efflux pump. However, unclear is its integral quantitative role in the overall epithelial drug transfer, which also involves distinct diffusion processes in parallel and sequence. We used a simple three-compartment model to obtain kinetic parameters of each drug transfer mechanism, which can quantitatively describe the transport time courses of P-gp substrates, digoxin and vinblastine, across P-gp-expressing MDCK cell monolayers grown on permeable filters. Our results show that the model, which assumes a functionally single drug efflux pump in the apical membrane with diffusion across two membranes and intercellular junctions, is the least complex model with which to quantitatively reproduce the characteristics of the data. Interestingly, the model predicts that the MDCK apical membranes are less diffusion permeable than the basolateral membrane for both drugs and that the distribution volume of vinblastine is 10-fold higher than that of digoxin. Additional experiments verified these model predictions. The modeling approach is feasible to quantitatively describe overall kinetic picture of epithelial drug transport. Further model refinement is necessary to incorporate other modes of drug transport such as transcytosis. Also, whether P-gp solely accounts for the pump function in this model awaits more studies.

scholarly journals Tetrandrine Interaction with ABCB1 Reverses Multidrug Resistance in Cancer Cells Through Competition with Anti-Cancer Drugs Followed by Downregulation of ABCB1 Expression

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4383 ◽  
Author(s):  
Dan Liao ◽  
Wei Zhang ◽  
Pranav Gupta ◽  
Zi-Ning Lei ◽  
Jing-Quan Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Cellular Localization ◽  
Treatment Time ◽  
Mrna Level ◽  
Chemotherapeutic Agents ◽  
Mdr1 Gene ◽  
P Glycoprotein ◽  
Abcb1 Transporter

The overexpression of ABC transporters induced by anticancer drugs has been found to be the main cause of multidrug resistance. It is actually also a strategy by which cancer cells escape being killed. Tetrandrine is a natural product extracted from the stem of Tinospora crispa. In this study, tetrandrine showed synergistic cytotoxic activity in combinational use with chemotherapeutic drugs, such as Doxorubicin, Vincristine, and Paclitaxel, in both drug-induced and MDR1 gene-transfected cancer cells that over-expressed ABCB1/P-glycoprotein. Tetrandrine stimulated P-glycoprotein ATPase activity, decreased the efflux of [3H]-Paclitaxel and increased the intracellular accumulation of [3H]-Paclitaxel in KB-C2 cells. Furthermore, SW620/Ad300 and KB-C2 cells pretreated with 1 μM tetrandrine for 72 h decreased P-glycoprotein expression without changing its cellular localization. This was demonstrated through Western blotting and immunofluorescence analysis. Interestingly, down-regulation of P-glycoprotein expression was not correlated with gene transcription, as the MDR1 mRNA level exhibited a slight fluctuation in SW620/Ad300 and KB-C2 cells at 0, 24, 48, and 72 h treatment time points. In addition, molecular docking analysis predicted that tetrandrine had inhibitory potential with the ABCB1 transporter. Our results suggested that tetrandrine can antagonize MDR in both drug-selected and MDR1 gene-transfected cancer cells by down regulating the expression of the ABCB1 transporter, followed by increasing the intracellular concentration of chemotherapeutic agents. The combinational therapy using tetrandrine and other anticancer drugs could promote the treatment efficiency of drugs that are substrates of ABCB1.

scholarly journals Structure and expression of the human MDR (P-glycoprotein) gene family.

1989 ◽  
Vol 9 (9) ◽  
pp. 3808-3820 ◽  
Author(s):  
J E Chin ◽  
R Soffir ◽  
K E Noonan ◽  
K Choi ◽  
I B Roninson
Keyword(s):  
Gene Family ◽  
Cell Lines ◽  
Efflux Pump ◽  
Expression Patterns ◽  
Multidrug Resistant ◽  
Resistant Cell ◽  
Mdr1 Gene ◽  
Glycoprotein Gene ◽  
P Glycoprotein ◽  
Mdr Genes

The human MDR (P-glycoprotein) gene family is known to include two members, MDR1 and MDR2. The product of the MDR1 gene, which is responsible for resistance to different cytotoxic drugs (multidrug resistance), appears to serve as an energy-dependent efflux pump for various lipophilic compounds. The function of the MDR2 gene remains unknown. We have examined the structure of the human MDR gene family by Southern hybridization of DNA from different multidrug-resistant cell lines with subfragments of MDR1 cDNA and by cloning and sequencing of genomic fragments. We have found no evidence for any other cross-hybridizing MDR genes. The sequence of two exons of the MDR2 gene was determined from genomic clones. Hybridization with single-exon probes showed that the human MDR1 gene is closely related to two genes in mouse and hamster DNA, whereas MDR2 corresponds to one rodent gene. The human MDR locus was mapped by field-inversion gel electrophoresis, and both MDR genes were found to be linked within 330 kilobases. The expression patterns of the human MDR genes were examined by enzymatic amplification of cDNA. In multidrug-resistant cell lines, increased expression of MDR1 mRNA was paralleled by a smaller increase in the levels of MDR2 mRNA. In normal human tissues, MDR2 was coexpressed with MDR1 in the liver, kidney, adrenal gland, and spleen. MDR1 expression was also detected in colon, lung, stomach, esophagus, muscle, breast, and bladder.

Saturable Function of P-Glycoprotein as a Drug-efflux Pump in Multidrug-resistant Tumour Cells

1996 ◽  
Vol 48 (5) ◽  
pp. 522-525 ◽  
Author(s):  
KEN-ICHI MIYAMOTO ◽  
KEIKO KOGA-TAKEDA ◽  
KENJIRO KOGA ◽  
TAEYUKI OHSHIMA ◽  
MASAAKI NOMURA
Keyword(s):  
Efflux Pump ◽  
Multidrug Resistant ◽  
Tumour Cells ◽  
Drug Efflux ◽  
P Glycoprotein ◽  
Drug Efflux Pump

scholarly journals Comparative Study of the Sensitivities of Cancer Cells to Doxorubicin, and Relationships between the Effect of the Drug-Efflux Pump P-gp

2014 ◽  
Vol 37 (12) ◽  
pp. 1926-1935 ◽  
Author(s):  
Golam Kibria ◽  
Hiroto Hatakeyama ◽  
Kosuke Akiyama ◽  
Kyoko Hida ◽  
Hideyoshi Harashima
Keyword(s):  
Comparative Study ◽  
Cancer Cells ◽  
Efflux Pump ◽  
Drug Efflux ◽  
Drug Efflux Pump
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