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Published on: April 26, 2018
Measurement of P-glycoprotein expression in human neuroblastoma xenografts using in vitro quantitative
R Fonti1, A Levchenko, B M Mehta
1Department of Nuclear Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Abstract:
P-glycoprotein (P-gp) has a role in multidrug resistance (MDR) encountered in human cancers. In this study, we used the colchicine-resistant cell line BE(2)-C/CHCb(0.2), a strain of neuroblastoma cell line BE(2)-C, as a model to measure variations of P-gp expression in cells grown in vitro and in vivo. Cells were cultured in the medium supplemented with colchicine. At the beginning of the study the drug was withdrawn and, after 22 days, added back to the culture medium. Cells were harvested at various time points and xenografted in nude mice. P-gp content in cells was measured by self-competitive binding assay and in tumors, by quantitative autoradiography (QAR). Both assays were carried out using 125I-labeled monoclonal antibody MRK16, reactive with P-gp. Concentration of P-gp in cells varied from a maximum of 1,361 pmol/g in the presence of colchicine to a minimum of 374 pmol/g in the absence of colchicine in the culture medium. P-gp concentration in the tumors ranged from 929 to 188 pmol/g, which correlated with P-gp content in the cells at the time of their injection in the mice. QAR is an accurate and reliable method to quantify P-gp expression in tumors. Changes in colchicine concentration in the ambient medium of BE(2)-C/CHCb(0.2) cells growing in vitro resulted in a change in phenotype of P-gp expression, which was stable under conditions of in vivo growth over approximately 9 cell divisions in nude mice xenografts. Therefore, P-gp content in xenografts depends only on the level of resistance of the cells at the time of their injection in the mice.
Insights
Multidrug resistance (MDR) in cancer involves P-glycoprotein (P-gp). This study shows P-gp expression in neuroblastoma cells changes with colchicine availability and remains stable in vivo, impacting xenograft P-gp levels.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- P-glycoprotein (P-gp) is crucial in multidrug resistance (MDR) in human cancers.
- Neuroblastoma is a pediatric cancer where MDR can limit treatment efficacy.
- Understanding P-gp expression dynamics is vital for developing effective cancer therapies.
Purpose of the Study:
- To investigate the variability of P-gp expression in a neuroblastoma cell line (BE(2)-C/CHCb(0.2)) under different in vitro and in vivo conditions.
- To assess the stability of P-gp expression in vivo after in vitro modulation.
- To evaluate quantitative autoradiography (QAR) as a method for P-gp quantification in tumors.
Main Methods:
- Utilized a colchicine-resistant neuroblastoma cell line (BE(2)-C/CHCb(0.2)) as a model.
- Manipulated P-gp expression in vitro by varying colchicine concentration in the culture medium.
- Xenografted cells into nude mice and quantified P-gp levels in cells and tumors using self-competitive binding assay and QAR with 125I-labeled MRK16 antibody.
Main Results:
- P-gp concentration in cells varied significantly, from 1,361 pmol/g with colchicine to 374 pmol/g without.
- Tumor P-gp concentrations ranged from 929 to 188 pmol/g, correlating with the P-gp level in cells at injection.
- P-gp expression phenotype remained stable in vivo for approximately 9 cell divisions.
Conclusions:
- Changes in the in vitro environment, specifically colchicine concentration, directly alter P-gp expression in neuroblastoma cells.
- P-gp expression levels in xenografts are determined by the cells' resistance phenotype prior to in vivo implantation.
- Quantitative autoradiography (QAR) is a reliable method for assessing P-gp expression in tumor xenografts.
