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Overlapping phenotypes of multidrug resistance among panels of human cancer-cell lines
M A Izquierdo1, R H Shoemaker, M J Flens
1Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
Abstract:
In addition to P-glycoprotein (Pgp), 2 proteins related to multidrug resistance (MDR) have recently been described. The Multidrug-Resistance-associated protein (MRP) is one of the ATP-binding-cassette (ABC) transporters. The Lung-Resistance Protein (LRP) is the major component of human vaults, which are newly described cellular organelles and thought to mediate intracellular transport processes. Using immunocytochemical methods, we have examined the expression of MRP and LRP among panels of human cancer-cell lines not selected for drug resistance which have been previously characterized for expression of Pgp, and in vitro response to a variety of anti-cancer drugs. Expression of MRP and LRP was observed in 47/55 (87%) and 46/59 (78%) cell lines, respectively. Statistically significant correlations were observed between expression of each of these 3 proteins and in vitro sensitivity to at least one drug classically associated with MDR. LRP showed the greatest individual predictive value, which also applied to several non-classical MDR drugs. Co-expression of 2-3 MDR-related proteins was observed in 64% of the lines and was, in general, associated with high relative levels of drug resistance. Previously identified "classic" MDR lines as well as "pan-resistant" lines concurrently expressed all 3 MDR-related proteins. Some highly drug-resistant cell lines without detectable MDRI/Pgp were found to express relatively high levels of MRP and LRP. The high prevalence of MRP and LRP expression observed in this large set of cell lines, which have not been subjected to laboratory drug selection, suggests that MDR mechanisms associated with these proteins may be widespread in human malignancies. Moreover, the overlapping of these more recently recognized MDR phenotypes with Pgp-type MDR results in a complex phenotype, the understanding of which may be of importance in the development of new drugs and design of clinical treatment protocols, particularly those seeking to employ strategies to reverse the MDR phenotype.
Insights
Multidrug resistance (MDR) proteins, Multidrug-Resistance-associated protein (MRP) and Lung-Resistance Protein (LRP), are frequently expressed in human cancers. Their co-expression correlates with drug resistance, impacting treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- P-glycoprotein (Pgp) is a known multidrug resistance (MDR) transporter.
- Multidrug-Resistance-associated protein (MRP) and Lung-Resistance Protein (LRP) are recently identified MDR-related proteins.
- LRP is a component of human vaults, involved in intracellular transport.
Purpose of the Study:
- To investigate the expression of MRP and LRP in human cancer cell lines.
- To correlate MRP and LRP expression with in vitro drug response.
- To understand the prevalence and impact of these MDR proteins in malignancies.
Main Methods:
- Immunocytochemical analysis of MRP and LRP expression.
- Utilized panels of human cancer cell lines previously characterized for Pgp expression.
- Assessed in vitro sensitivity to various anti-cancer drugs.
Main Results:
- MRP and LRP were expressed in 87% and 78% of cell lines, respectively.
- Significant correlations were found between MRP/LRP expression and in vitro sensitivity to MDR-associated drugs.
- Co-expression of 2-3 MDR proteins was linked to higher drug resistance levels.
- Some Pgp-negative cell lines showed high MRP and LRP expression.
Conclusions:
- MRP and LRP expression is widespread in human malignancies, suggesting common MDR mechanisms.
- The complex interplay of Pgp, MRP, and LRP contributes to a sophisticated MDR phenotype.
- Understanding these MDR mechanisms is crucial for developing novel anti-cancer drugs and treatment protocols.