P-Glycoprotein but not Topoisomerase II and Glutathione-S-Transferase-Pi Accounts for Enhanced Intracellular Drug-Resistance in LoVo MDR Human Cell Lines

1992 ◽  
Vol 78 (3) ◽  
pp. 159-166 ◽  
Author(s):  
Mauro Boiocchi ◽  
Loretta Tumiotto ◽  
Franca Giannini ◽  
Alessandra Viel ◽  
Gabriella Biscontin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Topoisomerase Ii ◽  
Resistance Mechanism ◽  
Parent Cell ◽  
Glutathione S Transferase ◽  
Intracytoplasmic Membrane ◽  
Human Colon Carcinoma Cell ◽  
P Glycoprotein ◽  
Drug Concentrations

The biochemical bases of the multidrug-resistant (MDR) phenotype were investigated in drug-resistant sublines derived from LoVo human colon carcinoma cell lines by doxorubicin (DOX) and teniposide (VM26) selection. In addition to P-glycoprotein-mediated drug extrusion through the plasma-membrane, LoVo MDR cells display a further drug-resistance mechanism. That is, to achieve equitoxic effects, LoVo MDR sublines require much higher intracellular drug concentrations than those required by LoVo drug-sensitive parent cell line. Involvement of mdr1, topoisomerase Il and glutathione-S-transferase-pi (GST-π) drug-resistance systems in intracellular drug resistance was investigated. Pharmacologic and biochemical data indicated that intracellular drug resistance in LoVo MDR sublines is uniquely consequent to the drug-transporting property of intracytoplasmic membrane-bound P-glycoprotein molecules which compartment drugs in vacuolelike structures.

scholarly journals Glutathione-S-transferase pi as a determinant of drug resistance in transfectant cell lines.

1990 ◽  
Vol 265 (8) ◽  
pp. 4296-4301
Author(s):  
K Nakagawa ◽  
N Saijo ◽  
S Tsuchida ◽  
M Sakai ◽  
Y Tsunokawa ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Glutathione S Transferase

Irinotecan Resistance – In Search of New Markers in CRC.

2021 ◽  
Author(s):  
Jakub Kryczka ◽  
Joanna Boncela
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Expression Profiles ◽  
Resistance Mechanism ◽  
Interaction Network ◽  
In Vitro Study ◽  
Cancer Drug ◽  
New Genes

Abstract Colorectal cancer (CRC) is one of the most prominent causes of cancer death worldwide. Chemotherapeutic regimens consisting of different drugs combinations such as 5-fluorouracil, and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) have been proven successful in the treatment of CRC. However, chemotherapy often leads to the acquisition of cancer drug resistance followed by metastasis and in the aftermath therapeutic failure. The molecular mechanism responsible for drug resistance is still unclear. The systemic search for new biomarkers of this phenomenon may identify new genes and pathways. To understand the drug resistance mechanism in CRC, the in vitro study based on the molecular analysis of drug-sensitive cells lines vs drug-resistant cells lines has been used. In our study to bridge the gap between in vitro and in vivo study, we compared the expression profiles of cell lines and patient samples from the publicly available database to select the new candidate genes for irinotecan resistance. Using The Gene Expression Omnibus (GEO) database of CRC cell lines (HT29, HTC116, LoVo, and their respective irinotecan-resistant variants) and patient samples (GSE42387, GSE62080, and GSE18105) we compared the changes in the mRNA expression profile of the main genes involved in irinotecan body’s processing, such as transport out of the cells and metabolism. Furthermore, using a protein-protein interaction network of differently expressed genes between FOLFIRI resistant and sensitive CRC patients, we have selected top networking proteins (upregulated: NDUFA2, SDHD, LSM5, DCAF4, and COX10, downregulated: RBM8A, TIMP1, QKI, TGOLN2, and PTGS2). Our analysis provided several potential irinotecan resistance markers, previously not described as such.

Reduced Response of IRE1α/Xbp-1 Signaling Pathway to Bortezomib Contributes to Drug Resistance in Multiple Myeloma Cells

2016 ◽  
Vol 103 (3) ◽  
pp. 261-267 ◽  
Author(s):  
Xiaoxuan Xu ◽  
Junru Liu ◽  
Beihui Huang ◽  
Meilan Chen ◽  
Shiwen Yuan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Resistance Mechanism ◽  
Proteasome Inhibition ◽  
Myeloma Cells ◽  
Potential Marker ◽  
Rpmi 8226 ◽  
Basic Level

Purpose Proteasome inhibition with bortezomib eliminates multiple myeloma (MM) cells by partly disrupting unfolded protein response (UPR). However, the development of drug resistance limits its utility and resistance mechanism remains controversial. We aimed to investigate the role of IRE1α/Xbp-1 mediated branch of the UPR in bortezomib resistance. Methods The expression level of Xbp-1s was measured in 4 MM cell lines and correlated with sensitivity to bortezomib. LP1 and MY5 cells with different Xbp-1s level were treated with bortezomib; then pivotal UPR regulators were compared by immunoblotting. RPMI 8226 cells were transfected with plasmid pEX4-Xbp-1s and exposed to bortezomib; then apoptosis was determined by immunoblotting and flow cytometry. Bortezomib-resistant myeloma cells JJN3.BR were developed and the effect on UPR signaling pathway was determined. Results By analyzing 4 MM cell lines, we found little correlation between Xbp-1s basic level and bortezomib sensitivity. Bortezomib induced endoplasmic reticulum stress-initiated apoptosis via inhibiting IRE1α/Xbp-1 pathway regardless of Xbp-1s basic level. Exogenous Xbp-1s reduced cellular sensitivity to bortezomib, suggesting the change of Xbp-1s expression, not its basic level, is a potential marker of response to bortezomib in MM cells. Furthermore, sustained activation of IRE1α/Xbp-1 signaling pathway in JJN3.BR cells was identified. Conclusions Our data indicate that reduced response of IRE1α/Xbp-1 signaling pathway to bortezomib may contribute to drug resistance in myeloma cells.

Cellular pharmacology of azatoxins (topoisomerase-II and tubulin inhibitors) in P-glycoprotein-positive and -negative cell lines

1995 ◽  
Vol 63 (2) ◽  
pp. 268-275 ◽  
Author(s):  
Beatrice Eymin ◽  
Eric Solary ◽  
Sylvie Chevillard ◽  
Laurence Dubrez ◽  
François Goldwasser ◽  
...  
Keyword(s):  
Cell Lines ◽  
Topoisomerase Ii ◽  
Tubulin Inhibitors ◽  
Cellular Pharmacology ◽  
Negative Cell ◽  
P Glycoprotein

Differential anthracycline sensitivity in two related human colon carcinoma cell lines expressing similar levels of P-glycoprotein

2001 ◽  
Vol 165 (1) ◽  
pp. 111-116 ◽  
Author(s):  
Alejandra L Boquete ◽  
Laura Vargas Roig ◽  
Gustavo A López ◽  
Rajiv Gude ◽  
M.Mercedes Binda ◽  
...  
Keyword(s):  
Colon Carcinoma ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Human Colon ◽  
Human Colon Carcinoma Cell ◽  
Carcinoma Cell Lines ◽  
Human Colon Carcinoma ◽  
P Glycoprotein

Low expression of topoisomerase II contributes to drug resistance of prostatic cancer-derived cell lines

1994 ◽  
Vol 5 ◽  
pp. 11
Author(s):  
I M Habler ◽  
G Theyer ◽  
T Thalhammer ◽  
G Baumgartner ◽  
G Hamilton
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Prostatic Cancer ◽  
Topoisomerase Ii ◽  
Low Expression

scholarly journals Correlation of P-glycoprotein expression and function in childhood acute leukemia: a children's cancer group study

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 309-318
Author(s):  
SP Ivy ◽  
RS Olshefski ◽  
BJ Taylor ◽  
KM Patel ◽  
GH Reaman
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Childhood Leukemia ◽  
Alkylating Agents ◽  
Chemotherapeutic Agents ◽  
Myelogenous Leukemia ◽  
Response To Treatment ◽  
Acute Leukemias ◽  
P Glycoprotein ◽  
And Function

Clinical drug resistance may be attributed to the simultaneous selection and expression of genes modulating the uptake and metabolism of chemotherapeutic agents. P-glycoprotein (P-gp) functions as a membrane-associated drug efflux pump whose increased expression results in resistance to anthracyclines, epipodophyllotoxins, vinca alkaloids, and some alkylating agents. This type of resistance occurs as both de novo and acquired resistance to therapy for leukemia. We have studied P- gp expression and function in childhood acute leukemias by developing a series of doxorubicin- and vincristine-selected CEM, T-cell lymphoblastoid cell lines that recapitulate the low levels of expression and resistance seen clinically. These cell lines have been used to develop flow cytometric assays for the semiquantitative measurements of P-gp expression with the MRK16 monoclonal antibody and P-gp function using the enhanced retention of rhodamine 123 in the presence of verapamil, a resistance modulator. Kolmogorov-Smirnov statistics, represented by the D measurement, are used to determine the difference in level of P-gp expression by comparing MRK16 staining to an IgG2a isotype control. When D is > 0.09, there is an excellent correlation (R = 0.82) between P-gp expression and function. The evaluation of 107 bone marrow specimens from 84 children with lymphoblastic or myelogenous leukemia showed a statistically significant (P = .004) increase in P-gp function at relapse. P-gp expression at relapse, however, approached but did not reach a significant level (P = .097). Using this methodology, we can identify patients with levels of P-gp expression and function that we can define clinically, as well as children with discordant multidrug resistance phenotypes. This study supports the role of P-gp-mediated drug resistance in childhood leukemia and confirms that P-gp expression and function are measurable in their leukemic blasts. These assays provide the means for the in vitro testing of resistance modulators and the monitoring of in vivo response to treatment with these agents.

scholarly journals Penetration of Candida Biofilms by Antifungal Agents

2004 ◽  
Vol 48 (9) ◽  
pp. 3291-3297 ◽  
Author(s):  
Mohammed A. Al-Fattani ◽  
L. Julia Douglas
Keyword(s):  
Drug Resistance ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Matrix Material ◽  
Resistance Mechanism ◽  
Single Species ◽  
Mixed Species ◽  
Drug Concentrations ◽  
Distal Edge ◽  
Major Drug

ABSTRACT A filter disk assay was used to investigate the penetration of antifungal agents through biofilms containing single and mixed-species biofilms containing Candida. Fluconazole permeated all single-species Candida biofilms more rapidly than flucytosine. The rates of diffusion of either drug through biofilms of three strains of Candida albicans were similar. However, the rates of drug diffusion through biofilms of C. glabrata or C. krusei were faster than those through biofilms of C. parapsilosis or C. tropicalis. In all cases, after 3 to 6 h the drug concentration at the distal edge of the biofilm was very high (many times the MIC). Nevertheless, drug penetration failed to produce complete killing of biofilm cells. These results indicate that poor antifungal penetration is not a major drug resistance mechanism for Candida biofilms. The abilities of flucytosine, fluconazole, amphotericin B, and voriconazole to penetrate mixed-species biofilms containing C. albicans and Staphylococcus epidermidis (a slime-producing wild-type strain, RP62A, and a slime-negative mutant, M7) were also investigated. All four antifungal agents diffused very slowly through these mixed-species biofilms. In most cases, diffusion was slower with biofilms containing S. epidermidis RP62A, but amphotericin B penetrated biofilms containing the M7 mutant more slowly. However, the drug concentrations reaching the distal edges of the biofilms always substantially exceeded the MIC. Thus, although the presence of bacteria and bacterial matrix material undoubtedly retarded the diffusion of the antifungal agents, poor penetration does not account for the drug resistance of Candida biofilm cells, even in these mixed-species biofilms.

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